Ann Neurol. 2022 Dec 26. doi: 10.1002/ana.26588. Online ahead of print.
OBJECTIVE: Polygenic variation accounts for a substantial portion of the risk of Alzheimer’s disease, 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 SNPs) from recent GWAS to generate a PGS. We assessed longitudinal tau-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. 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. This article is protected by copyright. All rights reserved.