Synergistic effects of APOE ε4 and Alzheimer’s pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE ε4, a key genetic risk factor for Alzheimer’s disease (AD). Although the presence of Aβ, tau, and APOE ε4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9±5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. Aβ was measured using CSF Aβ ₄₂ /Aβ ₄₀ or Florbetaben-PET imaging and tau was measured using CSF pTau ₁₈₁ . Hippocampal univariate activity and cortical reinstatement – that is, reinstatement of patterns of neocortical activity that were present during memory encoding – were measured during successful memory retrieval. Analyses revealed that APOE ε4 was independently associated with greater Aβ and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE ε4. Among APOE ε4 non-carriers, Aβ burden was linked to a pattern of hippocampal hyperactivity. Among APOE ε4 carriers, CSF pTau ₁₈₁ was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE ε4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD.