Abstract
Apolipoprotein E (APOE) ε4 is a major genetic risk factor for Alzheimer’s disease (AD), yet the mechanisms by which APOE-ε4 influences early-life brain function, and hence, in turn, risk for later-life AD, are poorly understood. Here, we report a novel, and selective, pattern of functional brain activity alteration in healthy young adult human APOE-ε4 carriers. Our findings suggest that APOE-ε4 may influence vulnerability to poorer later life cognitive health via its effect on posteromedial cortex (PMC), a hub region within a brain network involved in spatial processing, and necessary for episodic memory. In two neuroimaging tasks, APOE-ε4 carriers showed an inability to effectively modulate PMC during scene, but not face and object, working memory and perception. This striking pattern overlaps both functionally and topographically, with the earliest cognitive deficits seen in clinical AD, as well as reported alterations in the default network in amyloid-positive individuals at increased risk of AD.
Highlights
Apolipoprotein E (APOE) ε4 is a major genetic risk factor for Alzheimer’s disease (AD), yet the mechanisms by which APOE-ε4 influences early-life brain function, and in turn, risk for later-life AD, are poorly understood
Values were submitted to a two-way mixed model ANOVA, comprising a between-subjects factor of Group (APOE-ε 4 carriers; APOE-ε 4 non-carriers), and a within-subjects factor of Stimulus
In Task A, in which participants pressed a button when they noticed the immediate repeat of a scene, object, face or scrambled object, we found a significant difference between our APOE-ε 4 carrier and non-carrier groups in posteromedial cortex (PMC) regions (i.e., posterior cingulate cortex (PCC), precuneus and cingulate) in the scene condition only
Summary
Apolipoprotein E (APOE) ε4 is a major genetic risk factor for Alzheimer’s disease (AD), yet the mechanisms by which APOE-ε4 influences early-life brain function, and in turn, risk for later-life AD, are poorly understood. APOE-ε4 carriers showed an inability to effectively modulate PMC during scene, but not face and object, working memory and perception This striking pattern overlaps both functionally and topographically, with the earliest cognitive deficits seen in clinical AD, as well as reported alterations in the default network in amyloid-positive individuals at increased risk of AD. Older-aged individuals at increased genetic risk of AD (APOE-ε 4 allele carriers)[10] show disrupted DN activation and connectivity patterns[11,12,13] These DN brain modulations typically reflect a relative failure to deactivate PMC during memory encoding[8], a pattern that may explain the poor episodic memory characteristic of AD14. Task A: Visual working memory task Mean hit minus FA rate (S.D.) Scenes Faces Objects Scrambled objects Task B: Odd-one-out task Mean proportion correct (S.D.) Scenes Faces Objects Squared blocks Mean reaction time (S.D., ms) Scenes Faces Objects Squared blocks
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