Polygenic Effect on Tau Pathology Progression in Alzheimer's Disease

Abstract

Objective: Polygenic variation accounts for a substantial portion of the risk of Alzheimer's disease (AD), but its effect on the rate of fibrillar-tau accumulation as a key driver of dementia symptoms is unclear. Methods: We combined the to-date largest number of genetic risk variants of AD (n = 85 lead single-nucleotide polymorphisms [SNPs]) from recent genome-wide association studies (GWAS) to generate a polygenic score (PGS). We assessed longitudinal tau-positron emission tomography (PET), amyloid-PET, and cognition in 231 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using the PGS, together with global amyloid-PET, we predicted the rate of tau-PET increases in Braak-stage regions-of-interest and cognitive decline. We also assessed PGS-risk enrichment effects on the required sample size in clinical trials targeting tau pathology. Results: We found that a higher PGS was associated with higher rates of tau-PET accumulation, in particular at elevated amyloid-PET levels. The tau-PET increases mediated the association between PGS and faster cognitive decline. Risk enrichment through high PGS afforded sample size savings by 34%. Interpretation: Our results demonstrate that the PGS predicts faster tau progression and thus cognitive decline, showing utility to enhance statistical power in clinical trials. ANN NEUROL 2023;93:819–829.