Veronica Augustina Bot

All Publications

• Eight decades of follow-up link life course exposures to proteomic organ ageing and longevity. medRxiv : the preprint server for health sciences Groves, J. W., Bot, V. A., Ding, D. Y., Nicholas, J., Farinas, A., See-Oh, H., James, S., Wong, A., Williams, D. M., King-Robson, J., Chaturvedi, N., Richards, M., Wyss-Coray, T., Schott, J. M. 2025

  Abstract

  The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited1,2 and age-related diseases are leading causes of morbidity and mortality3. Proteomic clocks allow organ ageing to be estimated from blood sampling4, facilitating study of how life course exposures shape biological ageing heterogeneity. Here, we leverage the unique design of the MRC National Survey of Health and Development (NSHD), the world's oldest continuously followed birth cohort, to track 1,803 individuals across eight decades since birth in 1946. At mean age 63.2 years, we estimated proteomic ageing in seven organs. Despite near identical chronological ages, participants' proteomes revealed biological ageing disparities spanning decades. Extreme ageing in multiple organs was a strong prognostic indicator for all-cause mortality over the following 15 years (HR=6.62 for ≥ 4 extremely aged organs). Adversity and being overweight in adolescence associated with accelerated ageing decades later in life. Completing secondary school education and maintaining physical activity linked to relative biological youth. Mediation analyses indicated liver, kidney and immune ageing linked life course exposures to mortality. Across 10,776 plasma protein targets, we identified 143 predictors of longevity, including MED9, strongly linked to diverse socio-behavioural exposures. These findings provide unique insights into which factors are likely to shape how we age, when in life they may be influential, and how biological effects emerge, informing healthy ageing promotion.

  View details for DOI 10.1101/2025.09.07.25335188

  View details for PubMedID 40963758

• 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

• Reporting quality of heart failure randomized controlled trials 2000-2020: Temporal trends in adherence to CONSORT criteria. European journal of heart failure Jalloh, M. B., Bot, V. A., Borjaille, C. Z., Thabane, L., Li, G., Butler, J., Zannad, F., Granger, C. B., Van Spall, H. G. 2024; 26 (6): 1369-1380

  Abstract

  Heart failure (HF) is a major cause of morbidity and mortality in older adults. Randomized controlled trials (RCTs) inform HF policy and practice, but the accurate interpretation of results is contingent on clear and transparent reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement serves as a guide to RCT reporting. We evaluated the quality of reporting in HF RCTs in high-impact journals by assessing their adherence to CONSORT.We searched MEDLINE, EMBASE and CINAHL for HF RCTs published in high-impact journals 2000-2020. We assessed the proportion of CONSORT criteria that individual HF RCTs adhered to, and used the Jonckheere-Terpstra test to examine temporal trends in adherence. Multivariable linear regression explored the association between trial characteristics and adherence to CONSORT. Primary analysis assessed adherence to CONSORT 2010 update. A sensitivity analysis assessed adherence to the original (1996) CONSORT criteria. Among 221 RCTs analysed, the mean (standard deviation [SD]) adherence was suboptimal overall (mean [SD] adherence 69.7 [11.5]%) (5513/7913 criteria), with a temporal increase in adherence over the 20-year period (p < 0.001). Factors associated with adherence included publication after versus during/before 2010 (β = 10.17, 95% confidence interval [CI] 7.64-12.70; p < 0.001); two-group parallel individual-level randomization versus other (including multi-group or cluster randomization) (β = 5.81, 95% CI 2.88-8.73; p < 0.001); and multicentre versus single-centre trials (β = 7.26, 95% CI 3.25-11.27; p < 0.001). There was no difference in trial adherence to the updated CONSORT (2010) versus the original (1996) CONSORT criteria, and temporal trends in adherence to both sets of criteria were similar, likely due to overlap between the two sets of criteria. Trials with greater adherence to CONSORT were published in higher impact factor journals, with a positive correlation (r = 0.312; p < 0.001).The quality of reporting in HF RCTs, as measured by CONSORT adherence, has improved over time but remains suboptimal.

  View details for DOI 10.1002/ejhf.3229

  View details for PubMedID 38623814