Sex Differences in the Alzheimer’s Brain Age Gap: APOE ε4 Plays a Major Role
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INTRODUCTION
Brain age gap (BAG) is the difference between a person’s chronological age and the age predicted from the structural appearance of their brain on MRI. A higher BAG indicates an older-appearing brain and provides a global marker of structural brain aging across the Alzheimer’s disease continuum. Prior studies suggest that females may show greater Alzheimer’s disease-related pathology or faster late-stage neurodegeneration than males. We tested whether sex was associated with baseline BAG or longitudinal BAG change after accounting for APOE ε4 genetic risk, amyloid positivity, cognitive severity, and disease stage.
METHODS
We developed a domain-adaptive deep learning model to estimate BAG from T1-weighted MRIs, training it on 26,512 neurologically healthy UK Biobank data and fine-tuning it on 2,974 amyloid-negative cognitively normal samples from Mayo Clinic Study of Aging and OASIS-3 cohorts. We applied the model to ADNI and used hierarchical mixed-effects models to test whether sex was associated with BAG trajectories after adjusting for Alzheimer’s disease risk factors.
RESULTS
After adjustment for Alzheimer’s disease risk factors, there was no baseline sex differences in BAG. Longitudinally, females showed greater BAG acceleration than males, but this effect was moderated by APOE ε4 status. APOE ε4 accelerated brain aging in a dose-dependent manner, independent of amyloid burden.
DISCUSSION
Sex differences in BAG across the AD continuum were largely explained by APOE ε4-related acceleration rather than by an independent effect of sex alone. These findings suggest that females may be more vulnerable to APOE ε4-associated structural brain aging over time.
