ALZHEIMERS RESEARCH PROJECT: Biological pathways linking stress and brain aging: A multi-cohort pilot study of cognitive vulnerability and resilience

National Institute On Aging

Investigators

Abstract

This inter-laboratory project (LEPS × LBN) applies high-throughput plasma proteomics to uncover stress-related biological pathways relevant to midlife brain aging and cognitive vulnerability. We will profile ~11,000 proteins (SomaScan) in HANDLS, integrate allostatic load and perceived stress measures, and relate proteomic signatures to cognition and to MRI phenotypes (WMH; cortical thickness in AD-signature regions). Because the MRI subsample in HANDLS is relatively small, we will emphasize cognitive outcomes as primary endpoints, with MRI analyses providing complementary mechanistic insight. Cross-cohort replication in BLSA and ARIC will assess robustness and generalizability. FY2025 highlights: ILP approved budget: $100,000 (SomaLogic assay quoted at ~$44,550/plate; 81 samples/plate); Operating Budget added funds to total 5 plates. NIA Core Lab & Biorepository pull request prepared and awaiting Sample Pull Proteomics processing & harmonization planning with NIA Core Lab & Biorepository; November run window targeted. Analysis plan finalized for Aim 1 (stress → proteome), Aim 2 (proteome → cognition/MRI), Aim 3 (cross-cohort validation). Expected Results: Aim 1. Expect enriched inflammatory/vascular pathways with higher allostatic load and perceived stress, alongside resilience-related neurotrophic and antioxidant signals in lower-stress profiles. Aim 2. Anticipate that stress-linked proteins will show (a) adverse associations with cognitive performance and (b) positive associations with WMH burden and inverse associations with AD-signature cortical thickness. Aim 3. Predict replication in BLSA/ARIC, with cohort-dependent effect sizes reflecting sociodemographic context.