Sex‐specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia

Abstract INTRODUCTION Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.

Methods

We performed multimodal analyses of AD biomarker–positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth‐associated protein 43 (GAP‐43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.

Results

Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP‐43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.

Discussion

Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex‐specific disease trajectories and highlighting the need for sex‐informed biomarkers.