A cerebrospinal fluid synaptic protein biomarker for prediction of cognitive resilience versus decline in Alzheimer's disease.

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

SUBMITTER: Oh HS 

PROVIDER: S-EPMC12092275 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature