ABCA7 rs115550680 risk allele carriers have lower medial temporal lobe dynamic network flexibility than APOE-ε4 allele carriers among older African Americans

Alzheimer's disease (AD) pathology disrupts functional brain connectivity long before symptoms emerge. African Americans face elevated AD risk, yet underlying mechanisms remain unclear. Genetic risk differs by ancestry: APOE-ε4 strongly predicts late-onset AD in European ancestry, whereas ABCA7 rs115550680 confers substantial risk in African ancestry. Yet, how these variants influence neural function in African Americans is unclear. The medial temporal lobe (MTL) is an early target of AD pathology and resting-state functional Magnetic Resonance Imaging (rs-fMRI) measures of dynamic network connectivity (hereafter "flexibility"), the brain's capacity to dynamically reconfigure connectivity, provide a sensitive metric of network adaptability, potentially preceding structural decline. However, comparative influence of APOE-ε4 and ABCA7 rs115550680 on MTL flexibility and subregional volumes in this population is unknown. 146 older African Americans (Mean_Age=69.71 Mean_SD=6.29) were genotyped for APOE-ε4 and ABCA7 rs115550680 via saliva samples. Rs-fMRI was used to calculate MTL flexibility and T1-weighted MRI quantified MTL subregional volumes. ANCOVAs controlled for age, sex, and education, and APOE-ε4 when ABCA7 rs115550680 was the predictor. ABCA7 rs115550680 risk allele carriers exhibited lower MTL flexibility than non-carriers (p = .042) and APOE-ε4 allele carriers (p = .030). They also showed hypertrophy in left anterior hippocampus (p = .049), bilateral entorhinal cortex (ERC) (right p = .048; left p = .020) compared to non-carriers, and greater left ERC volume than APOE-ε4 allele carriers (p = .027). APOE-ε4 or interaction effects were not significant (p > .05). These findings provide preliminary evidence that ABCA7 rs115550680 risk allele, but not APOE-ε4 allele, is linked to reduced MTL flexibility and subregional hypertrophy in older African Americans, suggesting ancestry-specific mechanisms of early AD risk.