Sex differences in brain glucose metabolism in alzheimer's disease: A voxel-based study

A growing body of evidence shows significant sex differences in Alzheimer's Disease (AD) epidemiology, clinical presentation, and pathology burden; however, sex differences in neuroimaging biomarkers remain underexplored, prompting recent calls to action for more targeted research in this field. We analyzed static brain positron emission tomography (PET) imaging with 2-[¹⁸F] fluoro-2-deoxy-D-glucose (FDG) from 247 elderly individuals with AD dementia, including 151 women and 96 men. Voxel-based analysis was used to detect reductions in FDG uptake in each sex relative to a publicly shared normative database and to identify sex differences in FDG uptake within the AD cohort. Both sexes exhibited glucose hypometabolism in AD-vulnerable regions, including the parieto-temporal cortex, posterior cingulate, hippocampus, parahippocampal gyrus, and frontal lobes (P_FWE ≤ 0.001 in women and ≤ 0.013 in men). Sex differences in regional FDG uptake were observed in both directions, with greater hypometabolism in limbic and frontal regions in women (P_FWE ≤ 0.023) and in parietal cortices in men (P_FWE ≤ 0.008). The sex-specific distribution of hypometabolism, with more pronounced anterior involvement in women and posterior involvement in men, aligns with known differences in brain reserve and hormone-sensitive regions. This pattern suggests that neurophysiological and neuroendocrine aging may contribute to AD neuropathology in a sex-dependent manner. Recognizing these variations could refine diagnostic approaches and inform the development of sex-specific therapeutic strategies.