Sex specific differences of protein expression profiles in Alzheimer’s disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline and memory impairment, and it constitutes the most prevalent form of dementia worldwide. AD exhibits pronounced sex differences, with women showing a higher prevalence and faster disease progression compared to men. Despite growing recognition of these sex-specific disparities, the underlying molecular mechanisms contributing to differential susceptibility and pathology remain incompletely understood. In this study, we aimed to examine sex-specific differences in protein expression profiles within the entorhinal cortex (EC) of postmortem human brain samples, a region critically involved in memory formation and among the earliest affected during AD pathology. Postmortem brain tissues were obtained from donors pathologically diagnosed with AD (AD group) and age-matched non-AD controls (NC group). Proteins were extracted from EC samples and analyzed using high-throughput quantitative proteomics with tandem mass tag (TMT) labeling, which allows multiplexed, highly accurate, and reproducible quantification of protein abundance. A total of 4205 high-confidence proteins were identified across all AD and control samples, providing a comprehensive characterization of the proteomic landscape in this key brain region. Proteomic analysis revealed distinct protein expression patterns between female and male AD groups. Notably, 478 proteins were significantly altered in the female AD group compared with female controls, whereas only 113 proteins exhibited differential expression in the male AD group relative to male controls. These results indicate a broader and more pronounced proteomic dysregulation in female AD patients, suggesting that sex-specific molecular mechanisms may underlie the greater vulnerability observed in women. Further bioinformatic analysis identified 119 proteins that were significantly altered exclusively in the female AD group, but not in the mix or male AD groups. Among these, downregulated proteins are primarily involved in nervous system development and regulation processes, and are enriched in biological processes such as neuronal and axonal ensheathment, myelination, and glial cell generation and differentiation. Several key myelin-associated proteins, including myelin basic protein (MBP), 2ʹ,3ʹ-cyclic-nucleotide 3ʹ-phosphodiesterase (CNP), and myelin-associated glycoprotein (MAG), were significantly downregulated in female AD. The observed reduction in these proteins highlights a potential mechanism by which impaired myelin formation and maintenance may preferentially contribute to AD pathogenesis in women. Collectively, this study identifies sex-specific differences in the expression of myelin-associated proteins (MBP, CNP, and MAG) in AD, suggesting that impaired myelin formation may contribute to women’s increased susceptibility. These findings offer novel insights into the molecular pathology of AD and may inform the development of sex-tailored biomarkers and therapeutic strategies.