Precuneus Activity during Retrieval Is Positively Associated with Amyloid Burden in Cognitively Normal Older <i>APOE</i> 4 Carriers

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 (<i>APOE</i>) 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 <i>APOE</i>4 genotype. We included 165 older adults (age, 62.8 ± 4.4 years; 113 female; 66 <i>APOE</i>4 carriers) who were cognitively normal at baseline with a family history of AD. All participants performed task-fMRI at baseline and underwent ¹⁸F-flortaucipir-PET and ¹⁸F-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 <i>APOE</i>4 carriers but not noncarriers. We observed no effects of precuneus activity on tau burden. Finally, <i>APOE</i>4 noncarriers with low baseline precuneus activity exhibited better longitudinal performance in an independent memory test compared with (1) noncarriers with higher baseline activity and (2) <i>APOE</i>4 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 <i>APOE</i>4 carriers. Our results further indicate that the absence of "hyperactivation" and the absence of the <i>APOE</i>4 allele is related with better future cognitive outcomes in cognitively normal older adults at risk for AD.