Amelia Farinas

All Publications

• 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

• The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging. Nature medicine Imam, F., Saloner, R., Vogel, J. W., Krish, V., Abdel-Azim, G., Ali, M., An, L., Anastasi, F., Bennett, D., Pichet Binette, A., Boxer, A. L., Bringmann, M., Burns, J. M., Cruchaga, C., Dage, J. L., Farinas, A., Ferrucci, L., Finney, C. A., Frasier, M., Hansson, O., Hohman, T. J., Johnson, E. C., Kivimaki, M., Korologou-Linden, R., Ruiz Laza, A., Levey, A. I., Liepelt-Scarfone, I., Lu, L., Mattsson-Carlgren, N., Middleton, L. T., Nho, K., Oh, H. S., Petersen, R. C., Reiman, E. M., Robinson, O., Rothstein, J. D., Saykin, A. J., Shvetcov, A., Slawson, C., Smets, B., Suárez-Calvet, M., Tijms, B. M., Timmers, M., Vieira, F., Vilor-Tejedor, N., Visser, P. J., Walker, K. A., Winchester, L. M., Wyss-Coray, T., Yang, C., Bose, N., Lovestone, S. 2025

  Abstract

  More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.

  View details for DOI 10.1038/s41591-025-03834-0

  View details for PubMedID 40665048

  View details for PubMedCentralID 10625460

• 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

• 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

• Glia detect and transiently protect against dendrite substructure disruption in C. elegans. Nature communications Varandas, K. C., Hodges, B. M., Lubeck, L., Farinas, A., Liang, Y., Lu, Y., Shaham, S. 2025; 16 (1): 79

  Abstract

  Glia assess axon structure to modulate myelination and axon repair. Whether glia similarly detect dendrites and their substructures is not well understood. Here we show that glia monitor the integrity of dendrite substructures and transiently protect them against perturbations. We demonstrate that disruption of C. elegans sensory neuron dendrite cilia elicits acute glial responses, including increased accumulation of glia-derived extracellular matrix around cilia, changes in gene expression, and alteration of secreted protein repertoire. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, physically interact, and exhibit mutually-dependent localization to and around cilia, respectively. Glial responses to dendrite cilia disruption transiently protect against damage. Thus, our studies uncover a homeostatic, protective, dendrite-glia signaling interaction regulating dendrite substructure integrity.

  View details for DOI 10.1038/s41467-024-55674-0

  View details for PubMedID 39747235

  View details for PubMedCentralID PMC11696001