Polygenic effect on accelerated tau pathology accumulation in Alzheimer’s disease: implications for patient selection in clinical trials

Progression of fibrillar tau is a key driver of dementia symptoms in Alzheimer’s disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 – 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimer’s disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE ε4 genotype in clinical trials targeting tau pathology.