Longitudinal effects of sex differences and apolipoprotein E genotype on white matter engagement among elderly

The apolipoprotein E (<i>APOE</i>) ɛ4 allele is the primary genetic risk factor that influences lipid metabolism and contributes to distinctive Alzheimer's disease pathologies, including increased hippocampal atrophy and accelerated cognitive decline. Synaptic dysfunction can occur in <i>APOE4</i> carriers even before the appearance of any clinical symptoms. Recent evidence has suggested that this genetic risk factor impacts males and females differently. The sex-specific vulnerability for females to cognitive decline, particularly memory, intensifies post-menopause and emphasizes the need for further investigation. White matter abnormalities, <i>APOE4</i> allele and disruptions in default mode network connectivity serve as early indicators that are crucial for better understanding Alzheimer's disease progression. This study aims to explore relationships between biological sex, <i>APOE4</i>, default mode network-white matter activity and memory function as measured by the Selective Reminding Test. Participants were categorized by risk level on their <i>APOE4</i> status. Using longitudinal data from the Harvard Aging Brain Study, we examined sex differences in default mode network-white matter engagement among older individuals with and without the <i>APOE4</i> allele. Our findings demonstrated a significant reduction in default mode network-white matter activity in the right posterior corona radiata in the high-risk group compared to the low-risk group. High-risk females showed reduction in default mode network-white matter activity in the right superior longitudinal fasciculus, which positively correlated with free recall performance, compared to their low-risk counterparts. Unlike females, males showed no significant changes between the low- and high-risk groups. These results underscore the effectiveness of white matter engagement mapping in differentiating longitudinal changes in memory function related to the genetic risk factor <i>APOE4</i> and biological sex.