Abstract
Preclinical models of Alzheimer’s disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is a prominent cause of mortality in older populations
After controlling for fixed effects and familial confounds, we identified a positive association between AD-PRS and HC scene blood oxygen level dependent (BOLD) (β = 0.102; P = 0.016)
We sought to explore whether common AD risk alleles contribute to variation in HC BOLD during scene encoding in young healthy individuals
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is a prominent cause of mortality in older populations. Genome wide association studies (GWAS) demonstrate that AD is highly polygenic, explained by the cumulative effect of thousands of single nucleotide polymorphisms (SNPs) [1, 2]. The impact of these SNPs on human brain function is still poorly understood, especially in large-scale cohorts of young adults where a more detailed characterisation of the aetiology of AD is needed to determine the effectiveness of possible therapeutic targets. Population studies suggest a genetic overlap between AD and common genetic variation that influences cognitive ability across the lifespan [3, 4], suggesting that AD risk alleles influence the cognitive systems that support memory and intelligence. This work broadly suggests that variation within these genes are associated with task-related brain activity, in sub/cortical regions implicated in early AD associated Braakian atrophy including the hippocampus, entorhinal and cingulate cortices [5,6,7,8,9,10,11]
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