AbstractApolipoprotein 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.