Midlife brain vulnerability: Sex differences in functional magnetic resonance imaging and Alzheimer's disease risk

Midlife marks a critical period for detecting Alzheimer's disease (AD) risk because biological and lifestyle factors exceedingly influence brain aging. Konishi et al. used functional magnetic resonance imaging to examine sex differences and risk factors (apolipoprotein E (APOE) ε4, hypertension, type 2 diabetes, depression) on memory-related brain activity starting in midlife. High-risk women showed greater hippocampal hyperactivity, amyloid-β accumulation, and memory deficits than other groups. However, limited sample diversity, lack of tau imaging, unmeasured hormonal levels, and vascular influences constrain interpretations. These findings emphasize the need for sex-informed, mechanistically precise approaches in AD research targeting preclinical stages of disease progression.