Moderator of 1 Session
Presenter of 1 Presentation
POLYGENIC SCORE ASSOCIATED WITH ACCELERATED INCREASES IN TAU PET ACCUMULATION IN ALZHEIMER’S DISEASE
Abstract
Aims
Polygenic scores (PGS) are a powerful tool to combine the predictive value of GWAS-identified genetic variants, but the value to predict the rate of progression in tau pathology underlying cognitive worsening is unclear.
To test whether:
higher PGS is associated with longitudinal rates of tau PET.
PGS effects on tau progression were cell-type specific.
risk stratification by PGS is of utility for saving sample size in clinical trials on tau.
Methods
We leveraged the yet largest number of lead SNPs (n = 85) from two recent GWAS including up to 1.1 million participants (Bellenguez et al., 2020; Wightman et al., 2020) to estimate the PGS in over 1800 participants assessed by longitudinal composite memory scores and global cognition (average FU-duration = 4 yrs) and tau-PET (N = 231, average FU-duration = 2 yrs) from ADNI. In linear mixed effects models, we tested PGS to predict the rate of tau-PET in major Braak-stage ROIs and on cognitive decline.
Results
Higher PGS was associated with faster rates of increases in tau-PET, which was pronounced in amyloid-PET positive participants independent of APOE genotype. Faster tau-PET increases mediated PGS effects on cognitive decline. Cell-type specific PGS analysis implicated microglia and oligodendrocytes alterations in faster tau-PET progression. Risk stratification (> median PGS) reduced by 15% the required sample size to detect a 20%-treatment effect on tau-PET progression in amyloid-positive participants.
Conclusions
PGS is associated with faster increases in tau-PET and provides utility for risk stratification in disease-modifying treatments on tau.