Associations of genetic liability for Alzheimer's disease with cognition and eye movements in a large, population-based cohort study

Abstract

To identify cognitive measures that may be particularly sensitive to early cognitive decline in preclinical Alzheimer's disease (AD), we investigated the relation between genetic risk for AD and cognitive task performance in a large population-based cohort study. We measured performance on memory, processing speed, executive function, crystallized intelligence and eye movement tasks in 5182 participants of the Rhineland Study, aged 30 to 95 years. We quantified genetic risk for AD by creating three weighted polygenic risk scores (PRS) based on the genome-wide significant single-nucleotide polymorphisms coming from three different genetic association studies. We assessed the relation of AD PRS with cognitive performance using generalized linear models. Three PRS were associated with lower performance on the Corsi forward task, and two PRS were associated with a lower probability of correcting antisaccade errors, but none of these associations remained significant after correction for multiple testing. Associations between age and trail-making test A (TMT-A) performance were modified by AD genetic risk, with individuals at high genetic risk showing the strongest association. We conclude that no single measure of our cognitive test battery robustly captures genetic liability for AD as quantified by current PRS. However, Corsi forward performance and the probability of correcting antisaccade errors may represent promising candidates whose ability to capture genetic liability for AD should be investigated further. Additionally, our finding on TMT-A performance suggests that processing speed represents a sensitive marker of AD genetic risk in old age and supports the processing speed theory of age-related cognitive decline.

Fig. 1. Scatterplots for interaction effects between age and Alzheimer’s disease polygenic risk scores (PRS).

The scatterplots show how the associations between age and different cognitive outcomes vary with genetic risk for Alzheimer’s disease. Each column represents a different polygenic risk score and each row represents a cognitive outcome. The colours represent three different genetic risk groups for Alzheimer’s disease (orange = high risk/ z-standardized PRS score above 1; blue = medium risk/ z-standardised PRS score between −1 and 1; green = low risk/ z-standardised PRS score below −1). For each genetic risk group there exists one superimposed function for the development of the cognitive outcome across the adult life span. The functions were obtained from a multivariable regression model with the following formula: cognitive outcome ~ b₀ + age*b₁ + age²*b₂ + residual error. The grey area around the risk group-specific regression lines indicates the 95% confidence interval in each case. AVLT Auditory Verbal Learning and Memory Test; TMT-A Trail-making test A, N = number.