Polygenic risk score for Alzheimer’s disease and its association with eye movement performance

Abstract

AbstractBackgroundMany neurodegenerative disorders are characterised by changes in specific eye movement (EM) outcomes. Individuals with Alzheimer’s disease (AD) make more antisaccade errors and correct a lower proportion of those errors compared to controls. EM impairments occur at an early stage of neuropathological changes and have, therefore, been discussed as a potential biomarker. Despite high test‐retest correlations for measures of EM performance and an estimated heritability of >40% for antisaccade performance, genetic association studies identified only a few single‐nucleotide polymorphisms (SNPs) related to EM performance. Polygenic risk scores (PRSs) are advantageous as they summarize the effects of many SNPs into a single score. Therefore, we assessed whether higher genetic risk for AD in healthy participants was associated with higher antisaccade error rate and lower correction rate of antisaccade errors.MethodThe analyses were based on data of the first 2,000 participants (aged 30‐95) of the Rhineland Study, a community‐based prospective cohort study in Bonn, Germany. Genotyping was performed on Omni 2.5 exome arrays. We created PRS for AD by including all SNPs that reached genome‐wide significance at a threshold of p=5x10‐7in stage one of the GWAS of the “IGAP consortium”. Missing SNPs were imputed using the 1000 Genomes reference panel. We examined the association between genetic risk for AD and antisaccade error rate using multivariable regression with PRS as predictor and antisaccade error rate as outcome variables. For antisaccade correction rate we used a one‐inflated beta regression model as the residuals were severely skewed. Ancestry, age, age2, sex, visual acuity and education were added as covariates in both regression models.ResultPolygenic risk for AD was associated with neither antisaccade error rate nor the proportion of uncorrected errors in those who did not correct all of their errors. However, a higher PRS for AD was associated with a lower odds of correcting all mistakes (odds ratio=0.85 (95%‐CI:0.73‐1.00) per one standard deviation increase in PRS).ConclusionPolygenic risk for AD was associated with error correction rate in healthy individuals. Our findings suggest that eye movement performance may be a potential biomarker for early‐stage AD‐related neuropathological changes in the general population.