Abstract
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.
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This post is Copyright: | October 27, 2026
Neuro-Dementia