Pathway‐specific polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer's disease
Carolina Valentim, Jannis Denecke, Simon Frerich, Tobey J. Betthauser, Yuanxi Li, Reihaneh Ahmadi, Nicolai Franzmeier, , Rainer Malik, Michael EwersAbstract
BACKGROUND
Genome‐wide association studies (GWASs) identified multiple genetic variants associated with Alzheimer's disease (AD) risk, yet the biological pathways linking these to amyloid and tau pathology remain unclear.
METHODS
We conducted a meta‐analysis of recent GWASs to identify independent genome‐wide significant single nucleotide polymorphisms which were mapped via gene‐set enrichment to derive pathway‐specific polygenic risk scores (pPRSs). Analyses included 441 amyloid‐positive participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 224 with longitudinal tau positron emission tomography [PET]) and 250 amyloid‐positive participants from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study (113 with longitudinal tau PET). Robust linear regressions tested cross‐sectional and longitudinal pPRS‐by‐amyloid chronicity interactions on tau PET.
RESULTS
Four pPRSs were identified including adaptive immune response, leukocyte activation, transport, and intracellular signaling. Only the transport pPRS strengthened amyloid–tau coupling cross‐sectionally across all Braak stages in ADNI ( p < 0.05) and at Braak I in A4 ( p < 0.05), with stronger effects observed in females; in ADNI, these associations persisted longitudinally only at the higher Braak stages.
DISCUSSION
Genetic variation in transport pathways modulates amyloid‐driven tau accumulation, revealing mechanisms shaping AD progression, beyond apolipoprotein E.