The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E ( APOE ) genotype is unclear. Investigating the PREVENT-AD dataset, we assessed how baseline and longitudinal precuneus activity during successful memory retrieval relates to future Aβ and tau burden and change in memory performance. We further studied the moderation by APOE4 genotype. We included 165 older adults (age: 62.8±4.4 years; 113 female; 66 APOE4 carriers) who were cognitively normal at baseline with a family history of AD. All participants performed task-fMRI at baseline and underwent 18 F-flortaucipir-PET and 18 F-NAV4694-Aβ-PET on average 5 years later. We found that higher baseline activity and greater longitudinal increase in precuneus activity were associated with higher Aβ burden in APOE 4 carriers but not non-carriers. We observed no effects of precuneus activity on tau burden. Finally, APOE4 non-carriers with low baseline precuneus activity exhibited better longitudinal performance in an independent memory test compared to (i) non-carriers with higher baseline activity and (ii) APOE4 carriers. Our findings suggest that higher task-related precuneus activity during memory retrieval at baseline and over time are associated with greater Aβ burden in cognitively normal APOE4 carriers. Our results further indicate that the absence of “hyperactivation” and the absence of the APOE4 allele is related with better future cognitive outcomes in cognitively normal older adults at risk for AD. Significance Statement The precuneus, a brain region involved in episodic memory, is a site of early amyloid-beta (Aβ) accumulation. Alterations in task-related activity occur in the precuneus with aging and with Alzheimer’s disease (AD) pathology even in the absence of cognitive symptoms; however, their course and implications are not well understood. We demonstrate that higher precuneus activity at baseline and its change over time during successful memory retrieval is associated with higher Aβ burden on average 5 years after baseline in Apolipoprotein-E4 ( APOE4) carriers. Lower precuneus baseline activation was related to better longitudinal memory performance in APOE4 non-carriers. Our findings provide novel longitudinal evidence that increased activity in posterior midline regions is linked to early AD pathology in dependence of APOE4 genotype.

Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal olderAPOE4carriers