UNLABELLED

Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by ε4, a key genetic risk factor for Alzheimer's disease (AD). Although the presence of Aβ, tau, and 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 /Aβ or Florbetaben-PET imaging and tau was measured using CSF pTau . 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 ε4 was independently associated with greater Aβ and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by ε4. Among ε4 non-carriers, Aβ burden was linked to a pattern of hippocampal hyperactivity. Among ε4 carriers, CSF pTau 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 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.

SIGNIFICANCE STATEMENT

Hippocampus-dependent cortical reinstatement is a critical mechanism supporting episodic remembering that contributes to individual differences in memory performance in older adults. However, the contribution of early Alzheimer's disease (AD) pathology to variability in this mechanism is unknown. We demonstrate that associations of AD biomarkers with hippocampal activity and cortical reinstatement are moderated by ε4 in cognitively unimpaired older adults. Amyloid-β-related hyperactivity was observed in the hippocampus among ε4 non-carriers, while CSF pTau was linked to weaker cortical reinstatement during memory retrieval and lower memory performance among ε4 carriers. Our findings highlight synergistic effects of and AD pathology on brain function and identify candidate mechanisms that may underlie increased risk of memory impairment in preclinical AD.