Yann Le Guen

All Publications

• Long-read genome sequencing and multi-omics in aging and neurodegeneration. medRxiv : the preprint server for health sciences Jensen, T. D., Le Guen, Y., Talozzi, L., Yang, S., Gorzynski, J., Peña-Tauber, A., Stewart, I., Ferrasse, A., Nachun, D., Arriaga, M. T., Lee, J., Pulgrossi, R. C., Park, J., Zhang, J., Wagner, A. D., Mormino, E. C., Poston, K. L., Henderson, V. W., He, Z., Wyss-Coray, T., Montgomery, S. B., Ashley, E. A., Greicius, M. D. 2025

  Abstract

  Structural variants (SVs) are a major source of genetic variation yet remain underexplored in healthy aging and neurodegenerative diseases. We performed nanopore long-read genome sequencing (lrGS) on 551 deeply-phenotyped individuals from Stanford's Aging and Memory Study and Alzheimer's Disease Research Center, generating a comprehensive SV map integrated with matched methylation, transcriptomic, and proteomic data. Over 60% of SVs identified by lrGS were not detected with short-read WGS, including many poorly tagged by single-nucleotide variants (SNVs). We discovered >60,000 SV-QTLs across molecular traits and showed that SVs were more likely than SNVs to be fine-mapped as causal. Colocalization with Alzheimer's and Parkinson's disease GWAS implicated SVs at multiple loci, including TMEM106B, BIN3, and NBEAL1. Multi-omic outlier enrichment and Bayesian modeling prioritized rare functional SVs near known risk genes. Combined, these data reveal widespread regulatory SVs in healthy aging and neurodegeneration, underscoring the importance of lrGS in deciphering complex genetic architecture.

  View details for DOI 10.1101/2025.10.10.25337775

  View details for PubMedID 41282933

  View details for PubMedCentralID PMC12633103

• Plasma proteomics links brain and immune system aging with healthspan and longevity. Nature medicine Oh, H. S., Le Guen, Y., Rappoport, N., Urey, D. Y., Farinas, A., Rutledge, J., Channappa, D., Wagner, A. D., Mormino, E., Brunet, A., Greicius, M. D., Wyss-Coray, T. 2025

  Abstract

  Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.

  View details for DOI 10.1038/s41591-025-03798-1

  View details for PubMedID 40634782

  View details for PubMedCentralID 7301912

• Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes. Nature communications Park, J., Peña-Tauber, A., Talozzi, L., Greicius, M. D., Le Guen, Y. 2025; 16 (1): 2064

  Abstract

  Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one's susceptibility to cancer and/or early death.

  View details for DOI 10.1038/s41467-025-57315-6

  View details for PubMedID 40021682

  View details for PubMedCentralID 6218226

• Role of the X Chromosome in Alzheimer Disease Genetics. JAMA neurology Belloy, M. E., Le Guen, Y., Stewart, I., Williams, K., Herz, J., Sherva, R., Zhang, R., Merritt, V., Panizzon, M. S., Hauger, R. L., Gaziano, J. M., Logue, M., Napolioni, V., Greicius, M. D. 2024

  Abstract

  The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.To perform the first large-scale X chromosome-wide association study (XWAS) of AD.This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.Analyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome-wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.This large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.

  View details for DOI 10.1001/jamaneurol.2024.2843

  View details for PubMedID 39250132

• The Role of X Chromosome in Alzheimer's Disease Genetics. medRxiv : the preprint server for health sciences Belloy, M. E., Guen, Y. L., Stewart, I., Herz, J., Sherva, R., Zhang, R., Merritt, V., Panizzon, M. S., Hauger, R. L., Gaziano, J. M., Logue, M., Napolioni, V., Greicius, M. D. 2024

  Abstract

  The X chromosome has remained enigmatic in Alzheimer's disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.Perform the first large-scale X chromosome-wide association study (XWAS) of AD. Primary analyses are non-stratified, while secondary analyses evaluate sex-stratified effects.Meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP), the UK Biobank (UKB), the Finnish health registry (FinnGen), and the US Million Veterans Program (MVP). Risk for AD evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024.Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Summary statistics for multi-tissue expression and protein quantitative trait loci (QTL) available from published studies, enabling follow-up genetic colocalization analyses.1,629,863 eligible participants were selected from referred and volunteer samples, of which 477,596 were excluded for analysis exclusion criteria. Number of participants who declined to participate in original studies was not available.Risk for AD (odds ratio; OR) with 95% confidence intervals (CI). Associations were considered at X-chromosome-wide (P-value<1e-5) and genome-wide (P-value<5e-8) significance.Analyses included 1,152,284 non-Hispanic White European ancestry subjects (57.3% females), including 138,558 cases. 6 independent genetic loci passed X-chromosome-wide significance, with 4 showing support for causal links between the genetic signal for AD and expression of nearby genes in brain and non-brain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR=1.054, 95%-CI=[1.035, 1.075]) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes.We performed the first large-scale XWAS of AD and identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid beta accumulation. Overall, this study significantly advances our knowledge of AD genetics and may provide novel biological drug targets.

  View details for DOI 10.1101/2024.04.22.24306094

  View details for PubMedID 38712163

  View details for PubMedCentralID PMC11071554

• A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP. Neurology. Genetics Chemparathy, A., Le Guen, Y., Zeng, Y., Gorzynski, J., Jensen, T. D., Yang, C., Kasireddy, N., Talozzi, L., Belloy, M., Stewart, I., Gitler, A. D., Wagner, A. D., Mormino, E., Henderson, V. W., Wyss-Coray, T., Ashley, E., Cruchaga, C., Greicius, M. D. 2024; 10 (1): e200124

  Abstract

  Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on TMEM106B is the causal variant.An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an Alu element insertion on the 3'UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). Four hundred thirty-two individuals from 2 Stanford aging cohorts were whole-genome long-read and short-read sequenced. A total of 16,906 samples from ADSP were short-read sequenced. Genotypes, transcriptomics, and proteomics data were available in 1,979 participants from an aging and dementia cohort at WUSTL. Selection criteria were specific to each cohort. In primary analyses, the linkage disequilibrium between the TMEM106B locus variants in the FTLD-TDP GWAS and the 3'UTR insertion was estimated. We then estimated linkage by ancestry in the ADSP and evaluated the effect of the TMEM106B lead variant on mRNA and protein levels.The primary analysis included 432 participants (52.5% female, age range 45-92 years). We identified a 316 bp Alu insertion overlapping the TMEM106B 3'UTR tightly linked with top GWAS variants rs3173615(C) and rs1990622(A). In ADSP European ancestry participants, this insertion is in equivalent linkage with rs1990622(A) (R2 = 0.962, D' = 0.998) and rs3173615(C) (R2 = 0.960, D' = 0.996). In African ancestry participants, the insertion is in stronger linkage with rs1990622(A) (R2 = 0.992, D' = 0.998) than with rs3173615(C) (R2 = 0.811, D' = 0.994). In public data sets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL data set, rs1990622 is associated with TMEM106B protein levels in plasma and CSF, but not with TMEM106B mRNA expression.We identified a novel Alu element insertion in the 3'UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 3'UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies.

  View details for DOI 10.1212/NXG.0000000000200124

  View details for PubMedID 39911968

  View details for PubMedCentralID PMC10848896

• APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron Chemparathy, A., Le Guen, Y., Chen, S., Lee, E. G., Leong, L., Gorzynski, J. E., Jensen, T. D., Ferrasse, A., Xu, G., Xiang, H., Belloy, M. E., Kasireddy, N., Peña-Tauber, A., Williams, K., Stewart, I., Talozzi, L., Wingo, T. S., Lah, J. J., Jayadev, S., Hales, C. M., Peskind, E., Child, D. D., Roeber, S., Keene, C. D., Cong, L., Ashley, E. A., Yu, C. E., Greicius, M. D. 2024

  Abstract

  The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

  View details for DOI 10.1016/j.neuron.2024.01.008

  View details for PubMedID 38301647

• Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes. Proceedings of the National Academy of Sciences of the United States of America Le Guen, Y., Luo, G., Ambati, A., Damotte, V., Jansen, I., Yu, E., Nicolas, A., de Rojas, I., Peixoto Leal, T., Miyashita, A., Bellenguez, C., Lian, M. M., Parveen, K., Morizono, T., Park, H., Grenier-Boley, B., Naito, T., Küçükali, F., Talyansky, S. D., Yogeshwar, S. M., Sempere, V., Satake, W., Alvarez, V., Arosio, B., Belloy, M. E., Benussi, L., Boland, A., Borroni, B., Bullido, M. J., Caffarra, P., Clarimon, J., Daniele, A., Darling, D., Debette, S., Deleuze, J. F., Dichgans, M., Dufouil, C., During, E., Düzel, E., Galimberti, D., Garcia-Ribas, G., García-Alberca, J. M., García-González, P., Giedraitis, V., Goldhardt, O., Graff, C., Grünblatt, E., Hanon, O., Hausner, L., Heilmann-Heimbach, S., Holstege, H., Hort, J., Jung, Y. J., Jürgen, D., Kern, S., Kuulasmaa, T., Lee, K. H., Lin, L., Masullo, C., Mecocci, P., Mehrabian, S., de Mendonça, A., Boada, M., Mir, P., Moebus, S., Moreno, F., Nacmias, B., Nicolas, G., Niida, S., Nordestgaard, B. G., Papenberg, G., Papma, J., Parnetti, L., Pasquier, F., Pastor, P., Peters, O., Pijnenburg, Y. A., Piñol-Ripoll, G., Popp, J., Porcel, L. M., Puerta, R., Pérez-Tur, J., Rainero, I., Ramakers, I., Real, L. M., Riedel-Heller, S., Rodriguez-Rodriguez, E., Ross, O. A., Luís Royo, J., Rujescu, D., Scarmeas, N., Scheltens, P., Scherbaum, N., Schneider, A., Seripa, D., Skoog, I., Solfrizzi, V., Spalletta, G., Squassina, A., van Swieten, J., Sánchez-Valle, R., Tan, E. K., Tegos, T., Teunissen, C., Thomassen, J. Q., Tremolizzo, L., Vyhnalek, M., Verhey, F., Waern, M., Wiltfang, J., Zhang, J., Zetterberg, H., Blennow, K., He, Z., Williams, J., Amouyel, P., Jessen, F., Kehoe, P. G., Andreassen, O. A., Van Duin, C., Tsolaki, M., Sánchez-Juan, P., Frikke-Schmidt, R., Sleegers, K., Toda, T., Zettergren, A., Ingelsson, M., Okada, Y., Rossi, G., Hiltunen, M., Gim, J., Ozaki, K., Sims, R., Foo, J. N., van der Flier, W., Ikeuchi, T., Ramirez, A., Mata, I., Ruiz, A., Gan-Or, Z., Lambert, J. C., Greicius, M. D., Mignot, E. 2023; 120 (36): e2302720120

  Abstract

  Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

  View details for DOI 10.1073/pnas.2302720120

  View details for PubMedID 37643212

• A 3' UTR Deletion Is a Leading Candidate Causal Variant at the TMEM106B Locus Reducing Risk for FTLD-TDP. medRxiv : the preprint server for health sciences Chemparathy, A., Le Guen, Y., Zeng, Y., Gorzynski, J., Jensen, T., Kasireddy, N., Talozzi, L., Belloy, M. E., Stewart, I., Gitler, A. D., Wagner, A. D., Mormino, E., Henderson, V. W., Wyss-Coray, T., Ashley, E., Greicius, M. D. 2023

  Abstract

  Single nucleotide variants (SNVs) near TMEM106B have been associated with risk of frontotemporal lobar dementia with TDP pathology (FTLD-TDP) but the causal variant at this locus has not yet been isolated. The initial leading FTLD-TDP genome-wide association study (GWAS) hit at this locus, rs1990622, is intergenic and is in linkage disequilibrium (LD) with a TMEM106B coding SNV, rs3173615. We developed a long-read sequencing (LRS) dataset of 407 individuals in order to identify structural variants associated with neurodegenerative disorders. We identified a prevalent 322 base pair deletion on the TMEM106B 3' untranslated region (UTR) that was in perfect linkage with rs1990622 and near-perfect linkage with rs3173615 (genotype discordance in two of 274 individuals who had LRS and short-read next-generation sequencing). In Alzheimer's Disease Sequencing Project (ADSP) participants, this deletion was in greater LD with rs1990622 (R2=0.920916, D'=0.963472) than with rs3173615 (R2=0.883776, D'=0.963575). rs1990622 and rs3173615 are less closely linked (R2=0.7403, D'=0.9915) in African populations. Among African ancestry individuals in the ADSP, the deletion is in even greater LD with rs1990622 (R2=0.936841, D'=0.976782) than with rs3173615 (R2=0.764242, D'=0.974406). Querying publicly available genetic datasets with associated mRNA expression and protein levels, we confirmed that rs1990622 is consistently a protein quantitative trait locus but not an expression quantitative trait locus, consistent with a causal variant present on the TMEM106B 3'UTR. In summary, the TMEM106B 3' UTR deletion is a large genetic variant on the TMEM106B transcript that is in higher LD with the leading GWAS hit rs1990622 than rs3173615 and may mediate the protective effect of this locus in neurodegenerative disease.

  View details for DOI 10.1101/2023.07.06.23292312

  View details for PubMedID 37461476

  View details for PubMedCentralID PMC10350161

• Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease. JAMA Le Guen, Y., Raulin, A., Logue, M. W., Sherva, R., Belloy, M. E., Eger, S. J., Chen, A., Kennedy, G., Kuchenbecker, L., O'Leary, J. P., Zhang, R., Merritt, V. C., Panizzon, M. S., Hauger, R. L., Gaziano, J. M., Bu, G., Thornton, T. A., Farrer, L. A., Napolioni, V., He, Z., Greicius, M. D. 2023; 329 (7): 551-560

  Abstract

  Importance: Numerous studies have established the association of the common APOE epsilon2 and APOE epsilon4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.Design, Setting, and Participants: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.Exposures: Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.Main Outcomes and Measures: The primary outcome was AD case-control status, and secondary outcomes included age at AD onset.Results: Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In epsilon3/epsilon4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P=6.0*10-6) and was associated with a reported younger age at AD onset (beta, -5.87 years; 95% CI, -8.35 to -3.4 years; P=3.4*10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P=.04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P=.051). Association with earlier AD onset was replicated in stage 2 (beta, -5.23 years; 95% CI, -9.58 to -0.87 years; P=.02) and stage 3 (beta, -10.15 years; 95% CI, -15.66 to -4.64 years; P=4.0*10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.Conclusions and Relevance: In this exploratory analysis, the APOE epsilon3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the epsilon3/epsilon4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

  View details for DOI 10.1001/jama.2023.0268

  View details for PubMedID 36809323

• Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA neurology Le Guen, Y., Belloy, M. E., Grenier-Boley, B., de Rojas, I., Castillo-Morales, A., Jansen, I., Nicolas, A., Bellenguez, C., Dalmasso, C., Küçükali, F., Eger, S. J., Rasmussen, K. L., Thomassen, J. Q., Deleuze, J. F., He, Z., Napolioni, V., Amouyel, P., Jessen, F., Kehoe, P. G., van Duijn, C., Tsolaki, M., Sánchez-Juan, P., Sleegers, K., Ingelsson, M., Rossi, G., Hiltunen, M., Sims, R., van der Flier, W. M., Ramirez, A., Andreassen, O. A., Frikke-Schmidt, R., Williams, J., Ruiz, A., Lambert, J. C., Greicius, M. D., Arosio, B., Benussi, L., Boland, A., Borroni, B., Caffarra, P., Daian, D., Daniele, A., Debette, S., Dufouil, C., Düzel, E., Galimberti, D., Giedraitis, V., Grimmer, T., Graff, C., Grünblatt, E., Hanon, O., Hausner, L., Heilmann-Heimbach, S., Holstege, H., Hort, J., Jürgen, D., Kuulasmaa, T., van der Lugt, A., Masullo, C., Mecocci, P., Mehrabian, S., de Mendonça, A., Moebus, S., Nacmias, B., Nicolas, G., Olaso, R., Papenberg, G., Parnetti, L., Pasquier, F., Peters, O., Pijnenburg, Y. A., Popp, J., Rainero, I., Ramakers, I., Riedel-Heller, S., Scarmeas, N., Scheltens, P., Scherbaum, N., Schneider, A., Seripa, D., Soininen, H., Solfrizzi, V., Spalletta, G., Squassina, A., van Swieten, J., Tegos, T. J., Tremolizzo, L., Verhey, F., Vyhnalek, M., Wiltfang, J., Boada, M., García-González, P., Puerta, R., Real, L. M., Álvarez, V., Bullido, M. J., Clarimon, J., García-Alberca, J. M., Mir, P., Moreno, F., Pastor, P., Piñol-Ripoll, G., Molina-Porcel, L., Pérez-Tur, J., Rodríguez-Rodríguez, E., Royo, J. L., Sánchez-Valle, R., Dichgans, M., Rujescu, D. 2022

  Abstract

  The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.To determine whether rare missense variants on APOE are associated with AD risk.Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021.In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression.A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers.In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

  View details for DOI 10.1001/jamaneurol.2022.1166

  View details for PubMedID 35639372

• Common X-chromosome variants are associated with Parkinson's disease risk. Annals of neurology Le Guen, Y., Napolioni, V., Belloy, M. E., Yu, E., Krohn, L., Ruskey, J. A., Gan-Or, Z., Kennedy, G., Eger, S. J., Greicius, M. D. 2021

  Abstract

  OBJECTIVE: Identify genetic variants on the X-chromosome associated with Parkinson's disease (PD) risk.METHODS: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with: (i) PD risk in an independent replication with 1,561 cases and 2,465 controls, and (ii) putamen volume in 33,360 individuals from the UK Biobank.RESULTS: In the discovery meta-analysis, we identified: rs7066890 (OR=1.10 [1.06-1.14]; P=2.2x10-9 ) intron of GPM6B, and rs28602900 (OR=1.10 [1.07-1.14]; P=1.6x10-8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, PLXNA3. The rs28602900 association with PD was replicated (OR=1.16 [1.03-1.30]; P=0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in GTEx. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses.INTERPRETATION: We report the first XWAS of PD and identify two genome-wide significant loci. The rs28602900 association replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10.These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.26051

  View details for PubMedID 33583074

• Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics. American journal of human genetics He, Z., Le Guen, Y., Liu, L., Lee, J., Ma, S., Yang, A. C., Liu, X., Rutledge, J., Losada, P. M., Song, B., Belloy, M. E., Butler, R. R., Longo, F. M., Tang, H., Mormino, E. C., Wyss-Coray, T., Greicius, M. D., Ionita-Laza, I. 2021

  Abstract

  Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

  View details for DOI 10.1016/j.ajhg.2021.10.009

  View details for PubMedID 34767756

• Enhancer Locus in ch14q23.1 Modulates Brain Asymmetric Temporal Regions Involved in Language Processing. Cerebral cortex (New York, N.Y. : 1991) Le Guen, Y., Leroy, F., Philippe, C., Mangin, J. F., Dehaene-Lambertz, G., Frouin, V. 2020; 30 (10): 5322-5332

  Abstract

  Identifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homo sapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N = 16 515). This association was replicated in the IMAGEN cohort (N = 1726) and the UK Biobank non-British validation sample (N = 2161). This genomic region was also associated to a lesser extent with the right STAP depth and the formation of sulcal interruptions, "plis de passage," in the bilateral STAP but not with other structural brain MRI phenotypes, highlighting its notable association with the superior temporal regions. Diffusion MRI emphasized an association with the fractional anisotropy of the left auditory fibers of the corpus callosum and with networks involved in linguistic processing in resting-state functional MRI. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication.

  View details for DOI 10.1093/cercor/bhaa112

  View details for PubMedID 32432689

• eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data. Brain structure & function Le Guen, Y., Philippe, C., Riviere, D., Lemaitre, H., Grigis, A., Fischer, C., Dehaene-Lambertz, G., Mangin, J., Frouin, V. 2018

  Abstract

  The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer's disease in which brain shrinkage is a key biomarker.

  View details for DOI 10.1007/s00429-018-1808-9

  View details for PubMedID 30519892

• The chaotic morphology of the left superior temporal sulcus is genetically constrained NEUROIMAGE Le Guen, Y., Leroy, F., Auzias, G., Riviere, D., Grigis, A., Mangin, J., Coulon, O., Dehaene-Lambertz, G., Frouin, V. 2018; 174: 297–307

  Abstract

  The asymmetry of the superior temporal sulcus (STS) has been identified as a species-specific feature of the human brain. The so-called superior temporal asymmetrical pit (STAP) area is observed from the last trimester of gestation onwards and is far less pronounced in the chimpanzee brain. This asymmetry is associated with more frequent sulcal interruptions, named plis de passage (PPs), leading to the irregular morphology of the left sulcus. In this paper, we aimed to characterize the variability, asymmetry, and heritability of these interruptions in the STS in comparison with the other main sulci. We developed an automated method to extract PPs across the cortex based on a highly reproducible grid of sulcal pits across individuals, which we applied to a subset of Human Connectome Project (HCP) subjects (N = 820). We report that only a few PPs across the cortex are genetically constrained, namely in the collateral, postcentral and superior temporal sulci and the calcarine fissure. Moreover, some PPs occur more often in one hemisphere than the other, namely in the precentral, postcentral, intraparietal sulci, as well as in both inferior and superior temporal sulci. Most importantly, we found that only the interruptions within the STAP region are both asymmetric and genetically constrained. Because this morphological pattern is located in an area of the left hemisphere related to speech, our results suggest structural constraints on the architecture of the linguistic network.

  View details for DOI 10.1016/j.neuroimage.2018.03.046

  View details for Web of Science ID 000438609100026

  View details for PubMedID 29571714

• Genetic Influence on the Sulcal Pits: On the Origin of the First Cortical Folds CEREBRAL CORTEX Le Guen, Y., Auzias, G., Leroy, F., Noulhiane, M., Dehaene-Lambertz, G., Duchesnay, E., Mangin, J., Coulon, O., Frouin, V. 2018; 28 (6): 1922–33

  View details for DOI 10.1093/cercor/bhx098

  View details for Web of Science ID 000437164200002

• Ageing promotes microglial accumulation of slow-degrading synaptic proteins. Nature Guldner, I. H., Wagner, V. P., Moran-Losada, P., Shi, S. M., Golub, S. W., Hevler, J. F., Chen, K., Meese, B. T., Ghoochani, A., Pulido, E., Oh, H. S., Le Guen, Y., Lu, N., Wong, P. S., To, N. S., Garceau, D., Guo, Z., Luo, J., Bertozzi, C. R., Lundberg, E., Abu-Remaileh, M., Sasner, M., Keller, A., Yang, A. C., Cheung, T. H., Wyss-Coray, T. 2026

  Abstract

  Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing1,2. Here we engineered bioorthogonal tools3 that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

  View details for DOI 10.1038/s41586-025-09987-9

  View details for PubMedID 41565824

  View details for PubMedCentralID 3836174

• CD44 cross-linking promotes Plasmodium falciparum invasion. Nature communications Kongsomboonvech, A. K., Scally, S. W., Le Guen, Y., Valissery, P., Salinas, N. D., Cowman, A. F., Tolia, N. H., Egan, E. S. 2025

  Abstract

  The ability of Plasmodium falciparum to invade and replicate asexually within human red blood cells (RBCs) is central to its pathogenicity. Invasion involves several host-parasite interactions, yet the required host factors remain underexplored, largely due to the intractability of mature RBCs. The transmembrane protein CD44 was identified as a host factor for P. falciparum invasion through a novel forward genetic screen. Here, we identify an anti-CD44 monoclonal antibody, BRIC 222, that significantly promotes P. falciparum invasion through CD44 cross-linking. CD44 cross-linking induced changes in the phosphorylation of RBC cytoskeletal proteins, consistent with a proposed role for CD44 as a co-receptor during invasion. CD44 cross-linking also altered the RBC membrane, increasing the accessibility of several surface proteins, including the essential invasion receptor Basigin. The parasite ligand Erythrocyte Binding Antigen-175 (EBA-175), which interacts with CD44, enhanced P. falciparum invasion and induced RBC membrane changes similarly to BRIC 222. Moreover, both BRIC 222 and EBA-175 increased binding of the PfRH5/PCRCR invasion complex to Basigin, an interaction known to be essential for invasion. We propose that CD44 cross-linking, potentially by EBA-175, serves to coordinate and enhance ligand-receptor interactions and promote signaling to the host cell cytoskeleton, making RBCs more permissive to P. falciparum invasion.

  View details for DOI 10.1038/s41467-025-67030-x

  View details for PubMedID 41354647

• APOE*4 Risk-Modifying Genes and Drug Targets in Alzheimer's Disease through Cell-Type Specific Genomic Analyses. medRxiv : the preprint server for health sciences Zeng, Y., Cook, N., Yang, C., Sivasankaran, S. K., Fujita, M., Gardell, Z. A., Le Guen, Y., Shigemizu, D., Ozaki, K., Morizono, T., Hara, N., Miyashita, A., Ikeuchi, T., Pottier, C., Cruchaga, C., Napolioni, V., Corces, M. R., Menon, V., Greicius, M. D., Belloy, M. E. 2025

  Abstract

  APOE*4 is the strongest, common genetic risk factor for late-onset Alzheimer's disease (AD) with widespread and cell-type-specific impact on disease pathogenesis. Genetics and omics studies can help identify genes that counteract the effects of APOE*4, but so far have remained relatively small and crucially did not assess genetic findings through a cell-type-specific framework.Perform a large-scale APOE*4 stratified genome-wide association study (GWAS) of AD integrated with genetically tethered cell-type-specific multi-omics data.Meta-analysis of APOE*4 stratified AD GWAS in case-control, family-based, population-based, and longitudinal AD-related cohorts from the Alzheimer's Disease Genetics Consortium, Alzheimer's Disease Sequencing Project, and UK Biobank. Integration of GWAS with brain cell-type-specific genetic regulation of gene expression data, from the Religious Orders Study and Memory and Aging Project, to identify APOE*4 and cell-type-specific AD genes. Cell-type-specific multi-omics gene prioritization followed by compound and drug repurposing. Data analyzed between January 2023 and September 2025.Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Single-nucleus (sn) RNA-seq data from dorsolateral prefrontal cortex.567,521 eligible participants for AD genetic association studies were selected from referred and volunteer samples, of which 119,852 were excluded for analysis exclusion criteria.APOE*4 and cell-type-specific gene Z-scores and FDR-corrected P-values. Gene prioritization scores and APOE*4 stratified enriched compounds.67 and 17 significant cell-type-gene pairs were identified in APOE*4 non-carriers (APOE*4-) and carriers (APOE*4+) respectively. Oligodendrocytes displayed the largest proportion of APOE*4+ genes. 46 cell-type-gene pairs were supported by at least half of the gene prioritization analyses. Several prioritized genes were druggable and displayed enrichment of APOE*4 stratified drugs or compounds. Top APOE*4+ genes with connections to enriched drugs or compounds included TNS3 (astrocytes), CISD1 and SLC23A2 (oligodendrocytes), and UBXN4 (excitatory neurons).We identified a set of APOE*4 stratified genes that may be causal for AD through brain cell-type-specific mechanisms and prioritized top genes for further interrogation. We additionally identified compounds that may be repurposed or shed light on therapeutic avenues for treating AD based on an individual's APOE*4 status. Top identified compounds such as Hydrocortisone and Trolox implicate oxidative stress and neuroinflammation as potential biological targets in APOE*4+ individuals.

  View details for DOI 10.64898/2025.12.02.25341367

  View details for PubMedID 41404291

  View details for PubMedCentralID PMC12704626

• Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease. Molecular neurodegeneration Andersen, O. M., de Waal, M. W., Monti, G., Tesi, N., Jensen, A. M., de Geus, C., van Spaendonk, R., Vogel, M., Ahmad, S., Amin, N., Amouyel, P., Beecham, G. W., Bellenguez, C., Berr, C., Bis, J. C., Boland, A., Bossù, P., Bouwman, F., Bras, J., Charbonnier, C., Clarimon, J., Cruchaga, C., Daniele, A., Dartigues, J. F., Debette, S., Deleuze, J. F., Denning, N., DeStefano, A. L., Dols-Icardo, O., van Duijn, C. M., Farrer, L. A., Fernández, M. V., van der Flier, W. M., Fox, N. C., Galimberti, D., Genin, E., Gille, J. J., Grenier-Boley, B., Grozeva, D., Guen, Y. L., Guerreiro, R., Haines, J. L., Holmes, C., Hummerich, H., Arfan Ikram, M., Kamran Ikram, M., Kawalia, A., Kraaij, R., Lambert, J. C., Lathrop, M., Lemstra, A. W., Lleó, A., Myers, R. M., Mannens, M. M., Marshall, R., Martin, E. R., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Meggy, A., Mol, M. O., Nacmias, B., Naj, A. C., Napolioni, V., Nicholas Cochran, J., Nicolas, G., Pasquier, F., Pastor, P., Pericak-Vance, M. A., Pijnenburg, Y. A., Piras, F., Quenez, O., Ramirez, A., Raybould, R., Redon, R., Reinders, M. J., Richard, A. C., Riedel-Heller, S. G., Rivadeneira, F., van Rooij, J. G., Rousseau, S., Ryan, N. S., Sanchez-Juan, P., Schellenberg, G. D., Scheltens, P., Schott, J. M., Seshadri, S., Sie, D., Sims, R., Sistermans, E. A., Sorbi, S., van Swieten, J. C., Tijms, B., Uitterlinden, A. G., Visser, P. J., Wagner, M., Wallon, D., Wang, L. S., Williams, J., Yokoyama, J. S., Zarea, A., van der Lee, S. J., Olsen, J. G., Hulsman, M., Holstege, H. 2025; 20 (1): 122

  Abstract

  Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear.To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls.In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.Our results justify a debate on whether HPV carriers should be considered for clinical counseling.The online version contains supplementary material available at 10.1186/s13024-025-00907-z.

  View details for DOI 10.1186/s13024-025-00907-z

  View details for PubMedID 41327266

  View details for PubMedCentralID PMC12667055

• Spatial and single-cell transcriptomics reveal the reorganization of cerebellar microglia with aging. Cell reports Tsai, A. P., Henze, D. E., Ramirez Lopez, E., Haberberger, J., Dong, C., Lu, N., Atkins, M., Costa, E. K., Farinas, A., Oh, H. S., Moran-Losada, P., Le Guen, Y., Isakova, A., Quake, S. R., Wyss-Coray, T. 2025; 44 (12): 116624

  Abstract

  The cerebellum, essential for motor coordination and increasingly recognized for its role in cognition, is typically considered more resilient to aging and largely spared from hallmark Alzheimer's disease (AD) pathology. However, transcriptomic analyses across fifteen mouse brain regions revealed that the cerebellum undergoes some of the earliest and most pronounced age-related changes. To investigate cerebellar aging, we applied single-nucleus RNA sequencing (RNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH)-based spatial transcriptomics. Microglia showed the most prominent changes, including elevated expression of a neuroprotective signature and reduced expression of a lipid-droplet-accumulating signature compared to hippocampal microglia. Spatial analyses further revealed that aged cerebellar microglia were positioned in close proximity to granule cells. Utilizing this relationship, we identified a proximity-dependent transcriptional state defined by the neuron-associated microglial signature. This signature reveals a region-specific microglial adaptation, highlighting cerebellar reorganization with age and potential resilience to AD.

  View details for DOI 10.1016/j.celrep.2025.116624

  View details for PubMedID 41307999

• A CRISPR screen in enucleated human red cells identifies CLIC3 and VAMP8 as critical regulators of terminal erythropoiesis Tetard, M., Lin, T., Peterson, N., Gullberg, R., Le Guen, Y., Doench, J., Egan, E. ELSEVIER. 2025: 972-973

  View details for DOI 10.1182/blood-2025-972

  View details for Web of Science ID 001659261400023

• Integrative Genetic, Proteogenomic, and Multi-omics Analyses Reveal Sex-Biased Causal Genes and Drug Targets in Alzheimer's Disease. medRxiv : the preprint server for health sciences Cook, N., Yang, C., Zeng, Y., Sivasankaran, S. K., Song, S., Talozzi, L., Western, D., Yang, C., Liu, Y., Le Guen, Y., Stewart, I., Young, C., Mormino, E. C., Altmann, A., He, Z., Napolioni, V., Wingo, A. P., Wingo, T. S., Cruchaga, C., Sung, Y. J., Greicius, M. D., Belloy, M. E. 2025

  Abstract

  Sex differences are pervasive in Alzheimer's disease, but the underlying drivers remain poorly understood. To address this, we performed sex-stratified genome-wide association studies of Alzheimer's disease in ~1,000,000 individuals, which we subsequently integrated with proteogenomics datasets from neurological tissues to identify candidate causal genes. We further prioritized genes through additional multi-omics approaches, including quantitative trait locus summary-based mendelian randomization and colocalization. Altogether, we prioritized 125 female-biased and 21 male-biased risk genes. Female-biased pathways included amyloid, neurite, stress, clearance, and immune processes, with genes enriched for microglia and astrocyte expression. Through computational drug repurposing analyses, a set of sex hormone related drugs, converging on Epidermal Growth Factor Receptor (EGFR), were uniquely prioritized in women. Finally, we identified Haptoglobin (HP) as a female-specific gene, leveraging long-read sequencing approaches to implicate a link to oxidative stress, APOE, and hemoglobin biology. Altogether, our findings provide a portal into sex-specific precision medicine for Alzheimer's disease.

  View details for DOI 10.1101/2025.10.31.25339089

  View details for PubMedID 41282793

  View details for PubMedCentralID PMC12636628

• Cardiac Troponin Screening and Clinical Outcomes in Patients Receiving Immunotherapy. JACC. CardioOncology Cheng, E., Ivanovic, M., Chan, A., Xu, S., Franquiz, M., Lee, C., You, J., Fazal, M., Le Guen, Y., Batchelder, R., Reddy, S. A., Katsumoto, T., Ramchandran, K., Colevas, A. D., Kahn, S., Fan, A., Wakelee, H., Cheng, P., Lewis, E. F., Wu, S. M., Witteles, R., Neal, J., Waliany, S., Zhu, H. 2025

  Abstract

  Immune checkpoint inhibitors (ICIs) are associated with cardiotoxicities such as myocarditis. However, data on the implementation and outcomes of cardiac biomarker screening remain limited.The aim of this study was to examine the impact of cardiac troponin I (cTnI) surveillance integrated with symptom-based triaging in patients receiving immunotherapy.A single-center retrospective cohort study was conducted among adults who underwent routine serial cTnI monitoring during immunotherapy between January 2019 and October 2021. For patients with elevated cTnI, clinical presentation, management, and outcomes were analyzed. Major adverse cardiac events included arrhythmia, myocarditis, heart failure, acute coronary syndrome, stroke, and pericardial effusion. Patients were followed for 24 months from their first ICI dose.Among 428 patients (mean age 67.1 ± 13.9 years, 60.3% men), 42 (9.8%) had elevated cTnI detected through monitoring. Compared with symptomatic patients, asymptomatic patients more often underwent outpatient evaluation (88.0% vs 17.6%; P < 0.001) and continued immunotherapy (68.0% vs 35.3%; P < 0.001), whereas symptomatic patients more often underwent myocarditis-specific diagnostics such as cardiac magnetic resonance imaging (58.8% vs 8.0%; P = 0.001) and received immunosuppression (47.1% vs 8.0%; P = 0.008). The cumulative incidence of major adverse cardiac events at 1.5 years following cTnI elevation was 19.0% (95% CI: 7.0%-31.1%) and was significantly higher in symptomatic vs asymptomatic patients (subdistribution HR: 18.9; 95% CI: 2.2-162.5; P = 0.008). Symptomatic patients had a significantly higher risk for all-cause mortality at 2-year follow-up (HR: 3.24; 95% CI: 1.06-9.94; P = 0.04). In total, 6 patients were diagnosed with myocarditis, with no cardiac-related deaths.cTnI surveillance integrated with symptom-based triaging can facilitate early intervention and treatment of cardiotoxicities such as myocarditis.

  View details for DOI 10.1016/j.jaccao.2025.06.009

  View details for PubMedID 40810717

• CD44 cross-linking promotesPlasmodium falciparuminvasion. bioRxiv : the preprint server for biology Kongsomboonvech, A. K., Scally, S. W., Le Guen, Y., Valissery, P., Salinas, N. D., Cowman, A. F., Tolia, N. H., Egan, E. S. 2025

  Abstract

  The ability of the malaria parasite Plasmodium falciparum to invade and replicate asexually within human red blood cells (RBCs) is central to its pathogenicity, accounting for hundreds of thousands of deaths each year. RBC invasion is a multi-step process involving several host-parasite interactions, yet the host factors acting during invasion remain underexplored, largely due to the intractability of mature enucleated RBCs. The transmembrane protein CD44 was identified as a host factor for P. falciparum invasion through a forward genetic screen using genetically modified RBCs derived from primary human hematopoietic stem cells. Here, we identify an anti-CD44 monoclonal antibody, BRIC 222, that significantly promotes P. falciparum invasion, and demonstrate that its effect is mediated through CD44 cross-linking. CD44 cross-linking induced changes in the phosphorylation of RBC cytoskeletal proteins, consistent with a proposed role for CD44 as a co-receptor during invasion. CD44 cross-linking also altered the RBC membrane, increasing the accessibility of several surface proteins, including the essential invasion receptor Basigin. The parasite ligand Erythrocyte Binding Antigen-175 (EBA-175), which interacts with CD44, enhanced P. falciparum invasion and induced RBC membrane changes similarly to BRIC 222. Moreover, both BRIC 222 and EBA-175 increased binding of the PfRH5/PCRCR invasion complex to Basigin, an interaction known to be essential for invasion. We propose that CD44 cross-linking, potentially by EBA-175, serves to coordinate and enhance downstream ligand-receptor interactions and to promote signaling to the host cell cytoskeleton, making RBCs more permissive to P. falciparum invasion.

  View details for DOI 10.1101/2025.07.30.667750

  View details for PubMedID 40766538

• Disruption of the cerebrospinal fluid-plasma protein balance in cognitive impairment and aging. Nature medicine Farinas, A., Rutledge, J., Bot, V. A., Western, D., Ying, K., Lawrence, K. A., Oh, H. S., Yoon, S., Ding, D. Y., Tsai, A. P., Moran-Losada, P., Timsina, J., Le Guen, Y., Montgomery, S. B., Baker, D., Poston, K. L., Wagner, A. D., Mormino, E., Cruchaga, C., Wyss-Coray, T. 2025

  Abstract

  The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood-CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium. We identified proteins with correlated CSF and plasma levels that are produced primarily outside the brain and are enriched for structural domains that may enable their transport across brain barriers. CSF to plasma ratios of 848 proteins increased with aging in healthy control individuals, including complement and coagulation proteins, chemokines and proteins linked to neurodegeneration, whereas 64 protein ratios decreased with age, suggesting substrate-specific barrier regulation. Notably, elevated CSF to plasma ratios of peripherally derived or vascular-associated proteins, including DCUN1D1, MFGE8 and VEGFA, were associated with preserved cognitive function. Genome-wide association studies identified genetic loci associated with CSF to plasma ratios of 241 proteins, many of which have known disease associations, including FCN2, the collagen-like domain of which may facilitate blood-CSF transport. Overall, this work provides molecular insight into the human brain barrier system and its disruption with age and disease, with implications for the development of brain-permeable therapeutics.

  View details for DOI 10.1038/s41591-025-03831-3

  View details for PubMedID 40665050

  View details for PubMedCentralID 4015335

• Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations. Nature genetics Nicolas, A., Sherva, R., Grenier-Boley, B., Kim, Y., Kikuchi, M., Timsina, J., de Rojas, I., Dalmasso, M. C., Zhou, X., Le Guen, Y., Arboleda-Bustos, C. E., Camargos Bicalho, M. A., Guerchet, M., van der Lee, S., Goss, M., Castillo, A., Bellenguez, C., Küçükali, F., Satizabal, C. L., Fongang, B., Yang, Q., Peters, O., Schneider, A., Dichgans, M., Rujescu, D., Scherbaum, N., Deckert, J., Riedel-Heller, S., Hausner, L., Molina-Porcel, L., Düzel, E., Grimmer, T., Wiltfang, J., Heilmann-Heimbach, S., Moebus, S., Tegos, T., Scarmeas, N., Dols-Icardo, O., Moreno, F., Pérez-Tur, J., Bullido, M. J., Pastor, P., Sánchez-Valle, R., Álvarez, V., Cao, H., Ip, N. Y., Fu, A. K., Ip, F. C., Olivar, N., Muchnik, C., Cuesta, C., Campanelli, L., Solis, P., Politis, D. G., Kochen, S., Brusco, L. I., Boada, M., García-González, P., Puerta, R., Mir, P., Real, L. M., Piñol-Ripoll, G., García-Alberca, J. M., Royo, J. L., Rodriguez-Rodriguez, E., Soininen, H., Heikkinen, S., de Mendonça, A., Mehrabian, S., Traykov, L., Hort, J., Vyhnalek, M., Rasmussen, K. L., Thomassen, J. Q., Pijnenburg, Y. A., Holstege, H., van Swieten, J. C., Seelaar, H., Claassen, J. A., Jansen, W. J., Ramakers, I., Verhey, F., van der Lugt, A., Scheltens, P., Ortega-Rojas, J., Concha Mera, A. G., Mahecha, M. F., Pardo, R., Arboleda, G., Bahrami, S., Fominykh, V., Selbæk, G., Graff, C., Papenberg, G., Giedraitis, V., Boland, A., Deleuze, J. F., de Marco, L. A., de Moraes, E. N., de Mattos Viana, B., Túlio Gualberto Cintra, M., Juarez-Cedillo, T., Griswold, A. J., Forund, T., Haines, J., Farrer, L., DeStefano, A., Wijsman, E., Mayeux, R., Pericak-Vance, M., Kunkle, B., Goate, A., Schellenberg, G. D., Vardarajan, B., Wang, L. S., Leung, Y. Y., Dalgard, C. L., Nicolas, G., Wallon, D., Dufouil, C., Pasquier, F., Hanon, O., Debette, S., Grünblatt, E., Popp, J., Angel, B., Gloger, S., Chacon, M. V., Aranguiz, R., Orellana, P., Slachevsky, A., Gonzalez-Billault, C., Albala, C., Fuentes, P., Sachdev, P., Mather, K. A., Hauger, R. L., Merritt, V., Panizzon, M., Zhang, R., Gaziano, J. M., Ghidoni, R., Galimberti, D., Arosio, B., Mecocci, P., Solfrizzi, V., Parnetti, L., Squassina, A., Tremolizzo, L., Borroni, B., Nacmias, B., Caffarra, P., Seripa, D., Rainero, I., Daniele, A., Piras, F., Leonard, H. L., Yokoyama, J. S., Nalls, M. A., Miyashita, A., Hara, N., Ozaki, K., Niida, S., Williams, J., Masullo, C., Amouyel, P., Preux, P. M., Mbelesso, P., Bandzouzi, B., Saykin, A., Jessen, F., Kehoe, P. G., Van Duijn, C., Ben Salem, N., Frikke-Schmidt, R., Cherni, L., Greicius, M. D., Tsolaki, M., Sánchez-Juan, P., Romano Silva, M. A., Porter, T., Laws, S. M., Sleegers, K., Ingelsson, M., Dartigues, J. F., Seshadri, S., Rossi, G., Morelli, L., Hiltunen, M., Sims, R., van der Flier, W., Andreassen, O. A., Arboleda, H., Cruchaga, C., Escott-Price, V., Ruiz, A., Lee, K. H., Ikeuchi, T., Ramirez, A., Gim, J., Logue, M., Lambert, J. C. 2025

  Abstract

  A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

  View details for DOI 10.1038/s41588-025-02227-w

  View details for PubMedID 40533518

  View details for PubMedCentralID 8521998

• Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia. bioRxiv : the preprint server for biology Guldner, I. H., Wagner, V. P., Moran-Losada, P., Shi, S. M., Chen, K., Meese, B. T., Oh, H., Le Guen, Y., Lu, N., Wong, P. S., To, N. S., Garceau, D., Guo, Z., Luo, J., Sasner, M., Keller, A., Yang, A. C., Cheung, T., Wyss-Coray, T. 2025

  Abstract

  Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging1,2. We engineered bioorthogonal tools3 which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia. We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal 'aggregome' encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia. These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

  View details for DOI 10.1101/2025.05.20.654652

  View details for PubMedID 40475609

  View details for PubMedCentralID PMC12139995

• Resting Energy Expenditure Profiles in Pediatric Patients with Obesity Undergoing Sleeve Gastrectomy. Childhood obesity (Print) Koh, L., Kavarian, P., Le Guen, Y., Bruzoni, M., Pratt, J. S., Abu El Haija, M. 2025

  Abstract

  Background: Obesity is a prevalent medical condition among the pediatric population. Metabolic and bariatric surgery is recommended to treat severe obesity. Resting energy expenditure (REE) plays a vital role in weight homeostasis. This study aims to assess the impact of sleeve gastrectomy (SG) on REE in pediatric patients with severe obesity while comparing REE values with body composition. Methods: Participants were recruited from the Pediatric Weight Management Clinic and Bariatric Surgery Clinic at Lucile Packard Children's Hospital. REE was measured using indirect calorimetry. Body composition was assessed using dual energy X-ray absorptiometry scans. Data were collected prospectively and analyzed using a generalized linear model and correlation analyses. Results: Thirty-six participants with severe obesity were included. Correlation analyses showed significant differences in baseline REE/kg between age groups, with higher REE/kg in participants <16 years. No significant correlations were observed between pre-SG REE/kg and degree of weight loss post-SG. Pre-SG %lean body mass positively correlated with REE/kg. There was no significant change in REE/kg following SG with weight loss. Conclusions: SG remains an effective intervention for managing severe obesity. This study found no significant changes in REE after SG. Future research should focus on larger longitudinal studies to enhance understanding of the metabolic effects of SG in pediatric patients while optimizing strategies for improved health outcomes.

  View details for DOI 10.1089/chi.2024.0419

  View details for PubMedID 40331340

• A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease. Nature medicine Oh, H. S., Urey, D. Y., Karlsson, L., Zhu, Z., Shen, Y., Farinas, A., Timsina, J., Duggan, M. R., Chen, J., Guldner, I. H., Morshed, N., Yang, C., Western, D., Ali, M., Le Guen, Y., Trelle, A., Herukka, S. K., Rauramaa, T., Hiltunen, M., Lipponen, A., Luikku, A. J., Poston, K. L., Mormino, E., Wagner, A. D., Wilson, E. N., Channappa, D., Leinonen, V., Stevens, B., Ehrenberg, A. J., Gottesman, R. F., Coresh, J., Walker, K. A., Zetterberg, H., Bennett, D. A., Franzmeier, N., Hansson, O., Cruchaga, C., Wyss-Coray, T. 2025

  Abstract

  Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau181:Aβ42, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ+ and phosphorylated tau+ (A+T1+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T1+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10-4) and A+T1+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10-16) over a 15-year follow-up, adjusting for CSF pTau181:Aβ42, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

  View details for DOI 10.1038/s41591-025-03565-2

  View details for PubMedID 40164724

  View details for PubMedCentralID 8574196

• Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures across the Alzheimer disease continuum. Neuron Ali, M., Timsina, J., Western, D., Liu, M., Beric, A., Budde, J., Do, A., Heo, G., Wang, L., Gentsch, J., Schindler, S. E., Morris, J. C., Holtzman, D. M., Ruiz, A., Alvarez, I., Aguilar, M., Pastor, P., Rutledge, J., Oh, H., Wilson, E. N., Guen, Y. L., Khalid, R. R., Robins, C., Pulford, D. J., Tarawneh, R., Ibanez, L., Wyss-Coray, T., Sung, Y. J., Cruchaga, C. 2025

  Abstract

  Changes in β-amyloid (Aβ) and hyperphosphorylated tau (T) in brain and cerebrospinal fluid (CSF) precede Alzheimer's disease (AD) symptoms, making the CSF proteome a potential avenue to understand disease pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 analytes (2,029 unique proteins) dysregulated in AD. Of these, 865 (43%) were previously reported, and 1,164 (57%) are novel. The identified proteins cluster in four different pseudo-trajectories groups spanning the AD continuum and were enriched in pathways including neuronal death, apoptosis, and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfunction (mid stages), brain plasticity and longevity (mid stages), and microglia-neuron crosstalk (late stages). Using machine learning, we created and validated highly accurate and replicable (area under the curve [AUC] > 0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD.

  View details for DOI 10.1016/j.neuron.2025.02.014

  View details for PubMedID 40088886

• Additive association of blood group A allele with 15 cardiometabolic diseases: a UK Biobank life-course study. Cardiovascular diabetology Zhao, R., Xian, W., Ma, Y., Napolioni, V., Lau, P. W., Tian, X. L., Le Guen, Y., Franke, A., Huang, J. 2025; 24 (1): 113

  Abstract

  Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators.This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD.The additive model demonstrates a dose-response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10-96). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms.Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.

  View details for DOI 10.1186/s12933-025-02669-w

  View details for PubMedID 40065387

  View details for PubMedCentralID PMC11895148

• Plasma Aβ42/Aβ40 is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer's disease spectrum. Alzheimer's & dementia : the journal of the Alzheimer's Association Trelle, A. N., Young, C. B., Vossler, H., Ramos Benitez, J., Cody, K. A., Mendiola, J. H., Swarovski, M. S., Guen, Y. L., Feinstein, I., Butler, R. R., Channappa, D., Romero, A., Park, J., Shahid-Besanti, M., Corso, N. K., Chau, K., Smith, A. N., Skylar-Scott, I., Yutsis, M. V., Fredericks, C. A., Tian, L., Younes, K., Kerchner, G. A., Deutsch, G. K., Davidzon, G. A., Sha, S. J., Henderson, V. W., Longo, F. M., Greicius, M. D., Wyss-Coray, T., Andreasson, K. I., Poston, K. L., Wagner, A. D., Mormino, E. C., Wilson, E. N. 2024

  Abstract

  The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation.We evaluated fully-automated Lumipulse plasma Aβ42/Aβ40 immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ42/Aβ40 and cognition and cross-sectional associations with SAMS memory and tau positron emission tomography (PET) were examined.Plasma Aβ42/Aβ40 exhibited high performance in detecting amyloid positivity defined by PET (area under the curve [AUC]: 0.885, 95% confidence interval [CI]: 0.816-0.955). Once abnomal, plasma Aβ42/Aβ40 remained low and predicted cognitive decline in both CU and CI individuals. Among SAMS CU, plasma Aβ42/Aβ40 was associated with poorer hippocampal-dependent memory and elevated tau accumulation.Lumipulse plasma Aβ42/Aβ40 is a scalable assay for detection of cerebral Aβ and prediction of risk for cognitive decline across the AD continuum.Lumipulse plasma amyloid beta (Aβ)42/Aβ40 exhibited high accuracy in detecting amyloid positivity. Plasma amyloid-positive (Aβ+) individuals exhibited stability of Aβ42/Aβ40 over time. Plasma Aβ42/Aβ40 predicted future cognitive decline across the Alzheimer's disease (AD) spectrum. Plasma Aβ42/Aβ40 was sensitive to memory and tau burden in clinically unimpaired older adults.

  View details for DOI 10.1002/alz.14442

  View details for PubMedID 39713875

• Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference. Alzheimer's & dementia : the journal of the Alzheimer's Association Kloske, C. M., Mahinrad, S., Barnum, C. J., Batista, A. F., Bradshaw, E. M., Butts, B., Carrillo, M. C., Chakrabarty, P., Chen, X., Craft, S., Da Mesquita, S., Dabin, L. C., Devanand, D., Duran-Laforet, V., Elyaman, W., Evans, E. E., Fitzgerald-Bocarsly, P., Foley, K. E., Harms, A. S., Heneka, M. T., Hong, S., Huang, Y. A., Jackvony, S., Lai, L., Guen, Y. L., Lemere, C. A., Liddelow, S. A., Martin-Pena, A., Orr, A. G., Quintana, F. J., Ramey, G. D., Rexach, J. E., Rizzo, S. J., Sexton, C., Tang, A. S., Torrellas, J. G., Tsai, A. P., van Olst, L., Walker, K. A., Wharton, W., Tansey, M. G., Wilcock, D. M. 2024

  Abstract

  The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

  View details for DOI 10.1002/alz.14291

  View details for PubMedID 39692624

• Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease. Nature genetics Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., Gorijala, P., Kohlfeld, P., Budde, J., Levey, A. I., Morris, J. C., Perrin, R. J., Ruiz, A., Marquié, M., Boada, M., de Rojas, I., Rutledge, J., Oh, H., Wilson, E. N., Le Guen, Y., Reus, L. M., Tijms, B., Visser, P. J., van der Lee, S. J., Pijnenburg, Y. A., Teunissen, C. E., Del Campo Milan, M., Alvarez, I., Aguilar, M., Greicius, M. D., Pastor, P., Pulford, D. J., Ibanez, L., Wyss-Coray, T., Sung, Y. J., Cruchaga, C. 2024

  Abstract

  The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

  View details for DOI 10.1038/s41588-024-01972-8

  View details for PubMedID 39528825

  View details for PubMedCentralID 9605867

• Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference. Alzheimer's & dementia : the journal of the Alzheimer's Association Kloske, C. M., Belloy, M. E., Blue, E. E., Bowman, G. R., Carrillo, M. C., Chen, X., Chiba-Falek, O., Davis, A. A., Paolo, G. D., Garretti, F., Gate, D., Golden, L. R., Heinecke, J. W., Herz, J., Huang, Y., Iadecola, C., Johnson, L. A., Kanekiyo, T., Karch, C. M., Khvorova, A., Koppes-den Hertog, S. J., Lamb, B. T., Lawler, P. E., Guen, Y. L., Litvinchuk, A., Liu, C. C., Mahinrad, S., Marcora, E., Marino, C., Michaelson, D. M., Miller, J. J., Morganti, J. M., Narayan, P. S., Naslavsky, M. S., Oosthoek, M., Ramachandran, K. V., Ramakrishnan, A., Raulin, A. C., Robert, A., Saleh, R. N., Sexton, C., Shah, N., Shue, F., Sible, I. J., Soranno, A., Strickland, M. R., Tcw, J., Thierry, M., Tsai, L. H., Tuckey, R. A., Ulrich, J. D., van der Kant, R., Wang, N., Wellington, C. L., Weninger, S. C., Yassine, H. N., Zhao, N., Bu, G., Goate, A. M., Holtzman, D. M. 2024

  Abstract

  The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function.This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field.Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine.APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

  View details for DOI 10.1002/alz.13877

  View details for PubMedID 39031528

• Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity. bioRxiv : the preprint server for biology Oh, H. S., Le Guen, Y., Rappoport, N., Urey, D. Y., Rutledge, J., Brunet, A., Greicius, M. D., Wyss-Coray, T. 2024

  Abstract

  Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.

  View details for DOI 10.1101/2024.06.07.597771

  View details for PubMedID 38915561

  View details for PubMedCentralID PMC11195058

• Rare genetic variation in fibronectin 1 (FN1) protects against APOEepsilon4 in Alzheimer's disease. Acta neuropathologica Bhattarai, P., Gunasekaran, T. I., Belloy, M. E., Reyes-Dumeyer, D., Julich, D., Tayran, H., Yilmaz, E., Flaherty, D., Turgutalp, B., Sukumar, G., Alba, C., McGrath, E. M., Hupalo, D. N., Bacikova, D., Le Guen, Y., Lantigua, R., Medrano, M., Rivera, D., Recio, P., Nuriel, T., Ertekin-Taner, N., Teich, A. F., Dickson, D. W., Holley, S., Greicius, M., Dalgard, C. L., Zody, M., Mayeux, R., Kizil, C., Vardarajan, B. N. 2024; 147 (1): 70

  Abstract

  The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEepsilon4 allele. Elderly cognitively healthy individuals with APOEepsilon4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEepsilon4; however, these mechanisms are unknown. We hypothesized that APOEepsilon4 carriers without dementia might carry genetic variations that could protect them from developing APOEepsilon4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the NationalInstitute on Aging Alzheimer's Disease Family Based Study (NIA-ADFBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEepsilon4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEepsilon4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR=0.29; 95% CI [0.11, 0.78], P=0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P=0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEepsilon4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEepsilon4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEepsilon4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEepsilon4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b-the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEepsilon4, and LOF variants in FN1 may reduce APOEepsilon4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

  View details for DOI 10.1007/s00401-024-02721-1

  View details for PubMedID 38598053

• TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models. Nature neuroscience Wilson, E. N., Wang, C., Swarovski, M. S., Zera, K. A., Ennerfelt, H. E., Wang, Q., Chaney, A., Gauba, E., Ramos Benitez, J. A., Le Guen, Y., Minhas, P. S., Panchal, M., Tan, Y. J., Blacher, E., A Iweka, C., Cropper, H., Jain, P., Liu, Q., Mehta, S. S., Zuckerman, A. J., Xin, M., Umans, J., Huang, J., Durairaj, A. S., Serrano, G. E., Beach, T. G., Greicius, M. D., James, M. L., Buckwalter, M. S., McReynolds, M. R., Rabinowitz, J. D., Andreasson, K. I. 2024

  Abstract

  Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

  View details for DOI 10.1038/s41593-024-01610-w

  View details for PubMedID 38539014

  View details for PubMedCentralID 4369837

• In silico identification of putative causal genetic variants. bioRxiv : the preprint server for biology He, Z., Chu, B., Yang, J., Gu, J., Chen, Z., Liu, L., Morrison, T., Belloy, M. E., Qi, X., Hejazi, N., Mathur, M., Le Guen, Y., Tang, H., Hastie, T., Ionita-Laza, I., Sabatti, C., Candes, E. 2024

  Abstract

  Understanding the causal genetic architecture of complex phenotypes is essential for future research into disease mechanisms and potential therapies. Despite the widespread availability of genome-wide data, existing methods to analyze genetic data still primarily focus on marginal association models, which fall short of fully capturing the polygenic nature of complex traits and elucidating biological causal mechanisms. Here we present a computationally efficient causal inference framework for genome-wide detection of putative causal variants underlying genetic associations. Our approach utilizes summary statistics from potentially overlapping studies as input, constructs in silico knockoff copies of summary statistics as negative controls to attenuate confounding effects induced by linkage disequilibrium, and employs efficient ultrahigh-dimensional sparse regression to jointly model all genetic variants across the genome. Our method is computationally efficient, requiring less than 15 minutes on a single CPU to analyze genome-wide summary statistics. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimer's disease (AD) we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline via marginal association testing. The identified putative causal variants achieve state-of-the-art agreement with massively parallel reporter assays and CRISPR-Cas9 experiments. Additionally, we applied the method to a retrospective analysis of large-scale genome-wide association studies (GWAS) summary statistics from 2013 to 2022. Results reveal the method's capacity to robustly discover additional loci for polygenic traits beyond conventional GWAS and pinpoint potential causal variants underpinning each locus (on average, 22.7% more loci and 78.7% fewer proxy variants), contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses. We are making the discoveries and software freely available to the community and anticipate that routine end-to-end in silico identification of putative causal genetic variants will become an important tool that will facilitate downstream functional experiments and future research into disease etiology, as well as the exploration of novel therapeutic avenues.

  View details for DOI 10.1101/2024.02.28.582621

  View details for PubMedID 38464202

• Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer's disease. Research square Cruchaga, C., Ali, M., Shen, Y., Do, A., Wang, L., Western, D., Liu, M., Beric, A., Budde, J., Gentsch, J., Schindler, S., Morris, J., Holtzman, D., Fernandez, M., Ruiz, A., Alvarez, I., Aguilar, M., Pastor, P., Rutledge, J., Oh, H., Wilson, E., Le Guen, Y., Khalid, R., Robins, C., Pulford, D., Ibanez, L., Wyss-Coray, T., Ju Sung, Y. 2024

  Abstract

  Changes in Amyloid-beta (A), hyperphosphorylated Tau (T) in brain and cerebrospinal fluid (CSF) precedes AD symptoms, making CSF proteome a potential avenue to understand the pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 proteins dysregulated in AD, that were further validated in a third totally independent cohort. Machine learning was implemented to create and validate highly accurate and replicable (AUC>0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD and those AD cases with faster progression. The associated proteins cluster in four different protein pseudo-trajectories groups spanning the AD continuum and were enrichment in specific pathways including neuronal death, apoptosis and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfuncton(mid-stages), brain plasticity and longevity (mid-stages) and late microglia-neuron crosstalk (late stages).

  View details for DOI 10.21203/rs.3.rs-3631708/v1

  View details for PubMedID 38410465

• Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease. Molecular neurodegeneration Wang, L., Nykänen, N. P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., Brock, W., Marquié, M., Boada, M., Alvarez, I., Aguilar, M., Pastor, P., Ruiz, A., Puerta, R., Orellana, A., Rutledge, J., Oh, H., Greicius, M. D., Le Guen, Y., Perrin, R. J., Wyss-Coray, T., Jefferson, A., Hohman, T. J., Graff-Radford, N., Mori, H., Goate, A., Levin, J., Sung, Y. J., Cruchaga, C. 2024; 19 (1): 1

  Abstract

  Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

  View details for DOI 10.1186/s13024-023-00687-4

  View details for PubMedID 38172904

  View details for PubMedCentralID PMC10763080

• A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease. Cell reports Bharat, V., Durairaj, A. S., Vanhauwaert, R., Li, L., Muir, C. M., Chandra, S., Kwak, C. S., Le Guen, Y., Nandakishore, P., Hsieh, C. H., Rensi, S. E., Altman, R. B., Greicius, M. D., Feng, L., Wang, X. 2023; 42 (12): 113544

  Abstract

  Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.

  View details for DOI 10.1016/j.celrep.2023.113544

  View details for PubMedID 38060381

• Organ aging signatures in the plasma proteome track health and disease. Nature Oh, H. S., Rutledge, J., Nachun, D., Pálovics, R., Abiose, O., Moran-Losada, P., Channappa, D., Urey, D. Y., Kim, K., Sung, Y. J., Wang, L., Timsina, J., Western, D., Liu, M., Kohlfeld, P., Budde, J., Wilson, E. N., Guen, Y., Maurer, T. M., Haney, M., Yang, A. C., He, Z., Greicius, M. D., Andreasson, K. I., Sathyan, S., Weiss, E. F., Milman, S., Barzilai, N., Cruchaga, C., Wagner, A. D., Mormino, E., Lehallier, B., Henderson, V. W., Longo, F. M., Montgomery, S. B., Wyss-Coray, T. 2023; 624 (7990): 164-172

  Abstract

  Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

  View details for DOI 10.1038/s41586-023-06802-1

  View details for PubMedID 38057571

  View details for PubMedCentralID PMC10700136

• Modulation of the p75 neurotrophin receptor in the PS19 tauopathy mouse model regulates transcription profiles and inter-cellular communication across multiple populations of non-neuronal cells Butler, R. R., Yang, T., Han, C., Le Guen, Y., Tran, K. C., Lallani, S., Liu, H., Leng, S., Massa, S. M., Longo, F. M. WILEY. 2023

  View details for DOI 10.1002/alz.080789

  View details for Web of Science ID 001197662100003

• APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry. JAMA neurology Belloy, M. E., Andrews, S. J., Le Guen, Y., Cuccaro, M., Farrer, L. A., Napolioni, V., Greicius, M. D. 2023

  Abstract

  Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields.To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry.This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies.The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses.Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94).Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

  View details for DOI 10.1001/jamaneurol.2023.3599

  View details for PubMedID 37930705

  View details for PubMedCentralID PMC10628838

• Estimates of HIV testing at Visits to U.S. emergency departments, 2014-2020. AIDS (London, England) Clay, C. E., Hoover, K. W., Le Guen, Y., Bennett, C. L. 2023

  Abstract

  Emergency department (ED)-based HIV testing rates are historically low, but recent testing trends surrounding the COVID-19 pandemic and launch of the Ending the HIV Epidemic (EHE) initiative are unknown. The objective of the study is to estimate recent trends in the proportion of ED visits that included HIV testing.We performed a cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted nationally representative survey of US EDs, from 2014 to 2020. Given EHE's focus on several rural Southern jurisdictions as well as populations disproportionately affected by HIV, we stratified by characteristics including US region and visit-listed race and ethnicity.The proportion of ED visits that included HIV testing increased from 2014 (0.6%) to 2018 (1.1%) but was lower in 2019 and 2020 (0.8%). Compared to other regions the South had the lowest rates of testing in both 2019 (0.6%) and 2020 (0.5%); testing rates in the non-metropolitan South remained ≤0.1% across all years. Testing rates for ED visits by persons who identified as Hispanic/Latino were highest in 2018 (2.2%) but were sharply lower in 2019 and 2020 (0.8%).After a small but insufficient increase in ED-based HIV testing since 2014, rates decreased between 2018 and 2019 and were stable between 2019 and 2020. Overall, very few ED visits during our entire study period included an HIV test and there were persistently low rates of HIV testing for populations prioritized in national efforts and during visits in rural jurisdictions in the South.

  View details for DOI 10.1097/QAD.0000000000003750

  View details for PubMedID 37830905

• Loop diuretics association with Alzheimer's disease risk. Frontiers in aging Graber-Naidich, A., Lee, J., Younes, K., Greicius, M. D., Le Guen, Y., He, Z. 2023; 4: 1211571

  Abstract

  Objectives: To investigate whether exposure history to two common loop diuretics, bumetanide and furosemide, affects the risk of developing Alzheimer's disease (AD) after accounting for socioeconomic status and congestive heart failure. Methods: Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the de-identified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, and hypertension, and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases and 1,705 controls) were exposed to bumetanide. Results: After adjusting for socioeconomic status and other confounders, the exposure of bumetanide and furosemide was significantly associated with reduced AD risk (respectively, bumetanide odds ratio [OR] = 0.23; 95% confidence interval [CI], 0.15-0.36; p = 4.0 × 10-11; furosemide OR = 0.42; 95% CI, 0.38-0.47; p < 2.0 × 10-16). Discussion: Our study replicates in an independent sample that a history of bumetanide exposure is associated with reduced AD risk while also highlighting an association of the most common loop diuretic (furosemide) with reduced AD risk. These associations need to be additionally replicated, and the mechanism of action remains to be investigated.

  View details for DOI 10.3389/fragi.2023.1211571

  View details for PubMedID 37822457

  View details for PubMedCentralID PMC10563814

• Improving genetic risk prediction across diverse population by disentangling ancestry representations. Communications biology Gyawali, P. K., Le Guen, Y., Liu, X., Belloy, M. E., Tang, H., Zou, J., He, Z. 2023; 6 (1): 964

  Abstract

  Risk prediction models using genetic data have seen increasing traction in genomics. However, most of the polygenic risk models were developed using data from participants with similar (mostly European) ancestry. This can lead to biases in the risk predictors resulting in poor generalization when applied to minority populations and admixed individuals such as African Americans. To address this issue, largely due to the prediction models being biased by the underlying population structure, we propose a deep-learning framework that leverages data from diverse population and disentangles ancestry from the phenotype-relevant information in its representation. The ancestry disentangled representation can be used to build risk predictors that perform better across minority populations. We applied the proposed method to the analysis of Alzheimer's disease genetics. Comparing with standard linear and nonlinear risk prediction methods, the proposed method substantially improves risk prediction in minority populations, including admixed individuals, without needing self-reported ancestry information.

  View details for DOI 10.1038/s42003-023-05352-6

  View details for PubMedID 37736834

• APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology. Acta neuropathologica communications Talyansky, S., Le Guen, Y., Kasireddy, N., Belloy, M. E., Greicius, M. D. 2023; 11 (1): 149

  Abstract

  Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB-), sole LB pathology (AD-LB+), or no pathology (AD-LB-). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD-LB-), and compared the AD+LB+ to AD+LB- groups. APOE-ε4 was significantly associated with risk of AD+LB- and AD+LB+ compared to AD-LB-. However, APOE-ε4 was not associated with risk of AD-LB+ compared to AD-LB- or risk of AD+LB+ compared to AD+LB-. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.

  View details for DOI 10.1186/s40478-023-01626-6

  View details for PubMedID 37700353

  View details for PubMedCentralID PMC10496176

• Sex- and APOE-specific genetic risk factors for late-onset Alzheimer's disease: Evidence from gene-gene interaction of longevity-related loci. Aging cell Dato, S., De Rango, F., Crocco, P., Pallotti, S., Belloy, M. E., Le Guen, Y., Greicius, M. D., Passarino, G., Rose, G., Napolioni, V. 2023: e13938

  Abstract

  Advanced age is the largest risk factor for late-onset Alzheimer's disease (LOAD), a disease in which susceptibility correlates to almost all hallmarks of aging. Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene-gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to APOE*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, PTPN1, TXNRD1, and IGF1R were already found enriched in gene-gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex- and APOE-specific way. Indeed, while in APOE*4 female carriers we found several inter-pathway interactions, no significant epistasis was found in APOE*4 negative females; conversely, in males, significant intra- and inter-pathways epistasis emerged according to APOE*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex- and APOE-stratified preventive and therapeutic interventions for LOAD.

  View details for DOI 10.1111/acel.13938

  View details for PubMedID 37621137

• APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology. medRxiv : the preprint server for health sciences Chemparathy, A., Guen, Y. L., Chen, S., Lee, E. G., Leong, L., Gorzynski, J., Xu, G., Belloy, M., Kasireddy, N., Tauber, A. P., Williams, K., Stewart, I., Wingo, T., Lah, J., Jayadev, S., Hales, C., Peskind, E., Child, D. D., Keene, C. D., Cong, L., Ashley, E., Yu, C. E., Greicius, M. D. 2023

  Abstract

  The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). Knockdown of this allele may provide a therapeutic strategy for AD, but the effect of APOE loss-of-function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of older controls and patients with AD and identified six heterozygote carriers of APOE LoF variants. Five carriers were controls (ages 71-90) and one was an AD case with an unremarkable age-at-onset between 75-79. Two APOE ε3/ε4 controls (Subjects 1 and 2) carried a stop-gain affecting the ε4 allele. Subject 1 was cognitively normal at 90+ and had no neuritic plaques at autopsy. Subject 2 was cognitively healthy within the age range 75-79 and underwent lumbar puncture at between ages 75-79 with normal levels of amyloid. The results provide the strongest human genetics evidence yet available suggesting that ε4 drives AD risk through a gain of abnormal function and support knockdown of APOE ε4 or its protein product as a viable therapeutic option.

  View details for DOI 10.1101/2023.07.20.23292771

  View details for PubMedID 37547016

  View details for PubMedCentralID PMC10402217

• APOE - ε 4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology. medRxiv : the preprint server for health sciences Talyansky, S., Guen, Y. L., Kasireddy, N., Belloy, M. E., Greicius, M. D. 2023

  Abstract

  Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE - ε 4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD + LB + ), sole AD pathology (AD + LB - ), sole LB pathology (AD - LB + ), or no pathology (AD - LB - ). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD - LB - ), and compared the AD + LB + to AD + LB - groups. APOE - ε 4 was significantly associated with risk of AD + LB - and AD + LB + compared to AD - LB - . However, APOE - ε 4 was not associated with risk of AD - LB + compared to AD - LB - or risk of AD + LB + compared to AD + LB - . Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE - ε 4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.

  View details for DOI 10.1101/2023.04.21.23288938

  View details for PubMedID 37503074

  View details for PubMedCentralID PMC10371184

• Bumetanide Exposure Association with Alzheimer's Disease Risk. Research square Graber-Naidich, A., Lee, J., Younes, K., Greicius, M. D., Le Guen, Y., He, Z. 2023

  Abstract

  To investigate whether exposure history to two common loop diuretics affects the risk of developing Alzheimer's disease (AD) after accounting for socioeconomic status and congestive heart failure.Individuals exposed to bumetanide or furosemide were identified in the Stanford University electronic health record using the deidentified Observational Medical Outcomes Partnership platform. We matched the AD case cohort to a control cohort (1:20 case:control) on gender, race, ethnicity, hypertension and controlled for variables that could potentially be collinear with bumetanide exposure and/or AD diagnosis. Among individuals older than 65 years, 5,839 AD cases and 116,103 matched controls were included. A total of 1,759 patients (54 cases, 1,705 controls) were exposed to bumetanide.After adjusting for socioeconomic status and other confounders, bumetanide exposure was significantly associated with reduced AD risk (odds ratio = 0.50; 95% confidence interval, 0.37-0.68; p = 9.9×10-6), while the most common loop diuretics, furosemide, was not associated with AD risk.Our study replicates in an independent sample that history of bumetanide exposure is associated with reduced risk of AD and emphasizes that this association is not confounded by difference in socioeconomic status, which was an important caveat given the cost difference between bumetanide and furosemide.

  View details for DOI 10.21203/rs.3.rs-2574215/v1

  View details for PubMedID 36909637

  View details for PubMedCentralID PMC10002844

• GhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies. Nature communications He, Z., Liu, L., Belloy, M. E., Le Guen, Y., Sossin, A., Liu, X., Qi, X., Ma, S., Gyawali, P. K., Wyss-Coray, T., Tang, H., Sabatti, C., Candes, E., Greicius, M. D., Ionita-Laza, I. 2022; 13 (1): 7209

  Abstract

  Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) a meta-analysis for Alzheimer's disease comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies and (2) analysis of 1403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

  View details for DOI 10.1038/s41467-022-34932-z

  View details for PubMedID 36418338

• Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nature genetics Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., van Rooij, J. G., Sims, R., Ahmad, S., Amin, N., Norsworthy, P. J., Dols-Icardo, O., Hummerich, H., Kawalia, A., Amouyel, P., Beecham, G. W., Berr, C., Bis, J. C., Boland, A., Bosso, P., Bouwman, F., Bras, J., Campion, D., Cochran, J. N., Daniele, A., Dartigues, J., Debette, S., Deleuze, J., Denning, N., DeStefano, A. L., Farrer, L. A., Fernandez, M. V., Fox, N. C., Galimberti, D., Genin, E., Gille, J. J., Le Guen, Y., Guerreiro, R., Haines, J. L., Holmes, C., Ikram, M. A., Ikram, M. K., Jansen, I. E., Kraaij, R., Lathrop, M., Lemstra, A. W., Lleo, A., Luckcuck, L., Mannens, M. M., Marshall, R., Martin, E. R., Masullo, C., Mayeux, R., Mecocci, P., Meggy, A., Mol, M. O., Morgan, K., Myers, R. M., Nacmias, B., Naj, A. C., Napolioni, V., Pasquier, F., Pastor, P., Pericak-Vance, M. A., Raybould, R., Redon, R., Reinders, M. J., Richard, A., Riedel-Heller, S. G., Rivadeneira, F., Rousseau, S., Ryan, N. S., Saad, S., Sanchez-Juan, P., Schellenberg, G. D., Scheltens, P., Schott, J. M., Seripa, D., Seshadri, S., Sie, D., Sistermans, E. A., Sorbi, S., van Spaendonk, R., Spalletta, G., Tesi, N., Tijms, B., Uitterlinden, A. G., van der Lee, S. J., Visser, P. J., Wagner, M., Wallon, D., Wang, L., Zarea, A., Clarimon, J., van Swieten, J. C., Greicius, M. D., Yokoyama, J. S., Cruchaga, C., Hardy, J., Ramirez, A., Mead, S., van der Flier, W. M., van Duijn, C. M., Williams, J., Nicolas, G., Bellenguez, C., Lambert, J. 2022

  Abstract

  Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.

  View details for DOI 10.1038/s41588-022-01208-7

  View details for PubMedID 36411364

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• A Fast and Robust Strategy to Remove Variant-Level Artifacts in Alzheimer Disease Sequencing Project Data. Neurology. Genetics Belloy, M. E., Le Guen, Y., Eger, S. J., Napolioni, V., Greicius, M. D., He, Z. 2022; 8 (5): e200012

  Abstract

  Background and Objectives: Exome sequencing (ES) and genome sequencing (GS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer Disease Sequencing Project (ADSP) has taken a leading role in sequencing AD-related samples at scale, with the resultant data being made publicly available to researchers to generate new insights into the genetic etiology of AD. To achieve sufficient power, the ADSP has adapted a study design where subsets of larger AD cohorts are collected and sequenced across multiple centers, using a variety of sequencing platforms. This approach may lead to variable variant quality across sequencing centers and/or platforms. In this study, we sought to implement and evaluate filters that can be applied fast to robustly remove variant-level artifacts in the ADSP data.Methods: We implemented a robust quality control procedure to handle ADSP data. We evaluated this procedure while performing exome-wide and genome-wide association analyses on AD risk using the latest ADSP whole ES (WES) and whole GS (WGS) data releases (NG00067.v5).Results: We observed that many variants displayed large variation in allele frequencies across sequencing centers/platforms and contributed to spurious association signals with AD risk. We also observed that sequencing platform/center adjustment in association models could not fully account for these spurious signals. To address this issue, we designed and implemented variant filters that could capture and remove these center-specific/platform-specific artifactual variants.Discussion: We derived a fast and robust approach to filter variants that represent sequencing center-related or platform-related artifacts underlying spurious associations with AD risk in ADSP WES and WGS data. This approach will be important to support future robust genetic association studies on ADSP data, as well as other studies with similar designs.

  View details for DOI 10.1212/NXG.0000000000200012

  View details for PubMedID 35966919

• Deep neural networks with controlled variable selection for the identification of putative causal genetic variants NATURE MACHINE INTELLIGENCE Kassani, P. H., Lu, F., Le Guen, Y., Belloy, M. E., He, Z. 2022

  View details for DOI 10.1038/s42256-022-00525-0

  View details for Web of Science ID 000854675000002

• Deep neural networks with controlled variable selection for the identification of putative causal genetic variants. Nature machine intelligence Kassani, P. H., Lu, F., Guen, Y. L., Belloy, M. E., He, Z. 2022; 4 (9): 761-771

  Abstract

  Deep neural networks (DNNs) have been successfully utilized in many scientific problems for their high prediction accuracy, but their application to genetic studies remains challenging due to their poor interpretability. Here we consider the problem of scalable, robust variable selection in DNNs for the identification of putative causal genetic variants in genome sequencing studies. We identified a pronounced randomness in feature selection in DNNs due to its stochastic nature, which may hinder interpretability and give rise to misleading results. We propose an interpretable neural network model, stabilized using ensembling, with controlled variable selection for genetic studies. The merit of the proposed method includes: flexible modelling of the nonlinear effect of genetic variants to improve statistical power; multiple knockoffs in the input layer to rigorously control the false discovery rate; hierarchical layers to substantially reduce the number of weight parameters and activations, and improve computational efficiency; and stabilized feature selection to reduce the randomness in identified signals. We evaluate the proposed method in extensive simulation studies and apply it to the analysis of Alzheimer's disease genetics. We show that the proposed method, when compared with conventional linear and nonlinear methods, can lead to substantially more discoveries.

  View details for DOI 10.1038/s42256-022-00525-0

  View details for PubMedID 37859729

  View details for PubMedCentralID PMC10586424

• Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease. Neurology. Genetics Eger, S. J., Le Guen, Y., Khan, R. R., Hall, J. N., Kennedy, G., Zaharchuk, G., Couthouis, J., Brooks, W. S., Velakoulis, D., Napolioni, V., Belloy, M. E., Dalgard, C. L., Mormino, E. C., Gitler, A. D., Greicius, M. D. 1800; 8 (1): e647

  Abstract

  Objectives: The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).Methods: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.Results: The female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.Discussion: The results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

  View details for DOI 10.1212/NXG.0000000000000647

  View details for PubMedID 34901437

• Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping. Alzheimer's research & therapy Belloy, M. E., Eger, S. J., Le Guen, Y., Damotte, V., Ahmad, S., Ikram, M. A., Ramirez, A., Tsolaki, A. C., Rossi, G., Jansen, I. E., de Rojas, I., Parveen, K., Sleegers, K., Ingelsson, M., Hiltunen, M., Amin, N., Andreassen, O., Sánchez-Juan, P., Kehoe, P., Amouyel, P., Sims, R., Frikke-Schmidt, R., van der Flier, W. M., Lambert, J. C., He, Z., Han, S. S., Napolioni, V., Greicius, M. D. 2022; 14 (1): 22

  Abstract

  Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches.Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost.We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

  View details for DOI 10.1186/s13195-022-00962-4

  View details for PubMedID 35120553

• Identification of putative causal loci in whole-genome sequencing data via knockoff statistics. Nature communications He, Z., Liu, L., Wang, C., Le Guen, Y., Lee, J., Gogarten, S., Lu, F., Montgomery, S., Tang, H., Silverman, E. K., Cho, M. H., Greicius, M., Ionita-Laza, I. 2021; 12 (1): 3152

  Abstract

  The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

  View details for DOI 10.1038/s41467-021-22889-4

  View details for PubMedID 34035245

• A novel age-informed approach for genetic association analysis in Alzheimer's disease. Alzheimer's research & therapy Le Guen, Y., Belloy, M. E., Napolioni, V., Eger, S. J., Kennedy, G., Tao, R., He, Z., Greicius, M. D., Alzheimers Disease Neuroimaging Initiative 2021; 13 (1): 72

  Abstract

  BACKGROUND: Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.METHODS: Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).RESULTS: Modeling variable AD risk across age results in 5-10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes.CONCLUSION: Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

  View details for DOI 10.1186/s13195-021-00808-5

  View details for PubMedID 33794991

• Genome-wide haplotype association study in imaging genetics using whole-brain sulcal openings of 16,304 UK Biobank subjects EUROPEAN JOURNAL OF HUMAN GENETICS Karkar, S., Dandine-Roulland, C., Mangin, J., Le Guen, Y., Philippe, C., Deleuze, J., Pierre-Jean, M., Le Floch, E., Frouin, V. 2021; 29 (9): 1424-1437

  Abstract

  Neuroimaging-genetics cohorts gather two types of data: brain imaging and genetic data. They allow the discovery of associations between genetic variants and brain imaging features. They are invaluable resources to study the influence of genetics and environment in the brain features variance observed in normal and pathological populations. This study presents a genome-wide haplotype analysis for 123 brain sulcus opening value (a measure of sulcal width) across the whole brain that include 16,304 subjects from UK Biobank. Using genetic maps, we defined 119,548 blocks of low recombination rate distributed along the 22 autosomal chromosomes and analyzed 1,051,316 haplotypes. To test associations between haplotypes and complex traits, we designed three statistical approaches. Two of them use a model that includes all the haplotypes for a single block, while the last approach considers each haplotype independently. All the statistics produced were assessed as rigorously as possible. Thanks to the rich imaging dataset at hand, we used resampling techniques to assess False Positive Rate for each statistical approach in a genome-wide and brain-wide context. The results on real data show that genome-wide haplotype analyses are more sensitive than single-SNP approach and account for local complex Linkage Disequilibrium (LD) structure, which makes genome-wide haplotype analysis an interesting and statistically sound alternative to the single-SNP counterpart.

  View details for DOI 10.1038/s41431-021-00827-8

  View details for Web of Science ID 000625853200002

  View details for PubMedID 33664500

  View details for PubMedCentralID PMC8440755

• KLVS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE4 carriers. Neurobiology of aging Belloy, M. E., Eger, S. J., Le Guen, Y., Napolioni, V., Deters, K. D., Yang, H., Scelsi, M. A., Porter, T., James, S., Wong, A., Schott, J. M., Sperling, R. A., Laws, S. M., Mormino, E. C., He, Z., Han, S. S., Altmann, A., Greicius, M. D., A4 Study Team, Insight 46 Study Team, Australian Imaging Biomarkers and Lifestyle (AIBL) Study, Alzheimer's Disease Neuroimaging Initiative 2021; 101: 123–29

  Abstract

  KLOTHOVS heterozygosity (KLVSHET+) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE4 carriers. Additional studies suggest that KLVSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KLVSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE4 status. KLVSHET+ reduced the risk of amyloid positivity in APOE4 carriers (odds ratio= 0.67 [0.52-0.88]; p= 3.5*10-3), but not in APOE4 non-carriers (odds ratio= 0.94 [0.73-1.21]; p= 0.63). The combination of APOE4 and KLVS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE4 and AD are warranted.

  View details for DOI 10.1016/j.neurobiolaging.2021.01.008

  View details for PubMedID 33610961

• Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA neurology Belloy, M. E., Napolioni, V. n., Han, S. S., Le Guen, Y. n., Greicius, M. D. 2020

  Abstract

  Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear.To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4.This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019.The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04).The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.

  View details for DOI 10.1001/jamaneurol.2020.0414

  View details for PubMedID 32282020

• "Plis de passage" Deserve a Role in Models of the Cortical Folding Process BRAIN TOPOGRAPHY Mangin, J., Le Guen, Y., Labra, N., Grigis, A., Frouin, V., Guevara, M., Fischer, C., Riviere, D., Hopkins, W. D., Regis, J., Sun, Z. 2019

  Abstract

  Cortical folding is a hallmark of brain topography whose variability across individuals remains a puzzle. In this paper, we call for an effort to improve our understanding of the pli de passage phenomenon, namely annectant gyri buried in the depth of the main sulci. We suggest that plis de passage could become an interesting benchmark for models of the cortical folding process. As an illustration, we speculate on the link between modern biological models of cortical folding and the development of the Pli de Passage Frontal Moyen (PPFM) in the middle of the central sulcus. For this purpose, we have detected nine interrupted central sulci in the Human Connectome Project dataset, which are used to explore the organization of the hand sensorimotor areas in this rare configuration of the PPFM.

  View details for DOI 10.1007/s10548-019-00734-8

  View details for Web of Science ID 000488894700001

  View details for PubMedID 31583493

• Heritability of surface area and cortical thickness: a comparison between the Human Connectome Project and the UK Biobank dataset Le Guen, Y., Karkar, S., Grigis, A., Philippe, C., Mangin, J., Frouin, V., IEEE IEEE. 2019: 1887-1890

  View details for Web of Science ID 000485040000401

• Shared genetic aetiology between cognitive performance and brain activations in language and math tasks SCIENTIFIC REPORTS Le Guen, Y., Amalric, M., Pinel, P., Pallier, C., Frouin, V. 2018; 8: 17624

  Abstract

  Cognitive performance is highly heritable. However, little is known about common genetic influences on cognitive ability and brain activation when engaged in a cognitive task. The Human Connectome Project (HCP) offers a unique opportunity to study this shared genetic etiology with an extended pedigree of 785 individuals. To investigate this common genetic origin, we took advantage of the HCP dataset, which includes both language and mathematics activation tasks. Using the HCP multimodal parcellation, we identified areals in which inter-individual functional MRI (fMRI) activation variance was significantly explained by genetics. Then, we performed bivariate genetic analyses between the neural activations and behavioral scores, corresponding to the fMRI task accuracies, fluid intelligence, working memory and language performance. We observed that several parts of the language network along the superior temporal sulcus, as well as the angular gyrus belonging to the math processing network, are significantly genetically correlated with these indicators of cognitive performance. This shared genetic etiology provides insights into the brain areas where the human-specific genetic repertoire is expressed. Studying the association of polygenic risk scores, using variants associated with human cognitive ability and brain activation, would provide an opportunity to better understand where these variants are influential.

  View details for DOI 10.1038/s41598-018-35665-0

  View details for Web of Science ID 000452084600032

  View details for PubMedID 30514932

  View details for PubMedCentralID PMC6279777

• PyPNS: Multiscale Simulation of a Peripheral Nerve in Python. Neuroinformatics Lubba, C. H., Le Guen, Y., Jarvis, S., Jones, N. S., Cork, S. C., Eftekhar, A., Schultz, S. R. 2018

  Abstract

  Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help. We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modelled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modelled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin-Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.

  View details for DOI 10.1007/s12021-018-9383-z

  View details for PubMedID 29948844

• A study of feasibility for genome-wide haplotype association of complex traits in imaging genetics Karkar, S., Le Guen, Y., Philippe, C., Dandine-Roulland, C., Pierre-Jean, M., Mangin, J., Le Floch, E., Frouin, V. edited by Zheng, H., Callejas, Z., Griol, D., Wang, H., Hu, Schmidt, H., Baumbach, J., Dickerson, J., Zhang, L. IEEE. 2018: 2764-2766

  View details for Web of Science ID 000458654000480

• Regional Study of the Genetic Influence on the Sulcal Pits Le Guen, Y., Auzias, G., Dehaene-Lambertz, G., Leroy, F., Mangin, J., Duchesnay, E., Coulon, O., Frouin, V., IEEE IEEE. 2017: 77-80

  View details for Web of Science ID 000414283200019