Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older APOE4 carriers

The precuneus is an early site of 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) risk stages are lacking and the interaction with Apolipoprotein-E ( APOE ) genotype is unclear. In the PREVENT-AD cohort, we assessed how precuneus activity during successful memory retrieval at baseline and over time relates to future Aβ and tau burden and to 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 and had 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 change in activity in precuneus were associated with higher subsequent Aβ in APOE 4 carriers but not non-carriers. There were no effects of precuneus activity on tau burden. Finally, APOE4 non-carriers with low baseline activity in the precuneus exhibited better longitudinal performance in an independent memory test compared to APOE4 non-carriers with high baseline activity and APOE4 carriers. Our findings suggest that higher task-related precuneus activity at baseline and over time are associated with subsequent 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 the best future cognitive outcome in cognitively normal older adults at risk for AD.