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Ciencia básica y patogénesis
Alexander M Kulminski1, Fan Feng1, Irina Kulminskaya1
1Social Science Research Institute, Duke University, Durham, NC, USA.
Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 24, 2025
Resumen
La susceptibilidad genética a la enfermedad de Alzheimer (EA) y la diabetes mellitus (DM) muestra diferencias sexuales significativas. Los estudios de asociación de genoma completo revelan loci genéticos distintos que influyen en el riesgo de EA y DM en hombres y mujeres, destacando el papel de la heterogeneidad genética.
Área de la Ciencia:
- Genetics; Neuroscience; Endocrinology
Sus antecedentes:
- Alzheimer's disease (AD) affects women more than men, but survival rates don't fully explain this disparity.; Genetic factors significantly contribute to AD heritability, necessitating research into sex-specific genetic influences on AD and its risk factors.; Understanding sex differences in AD and diabetes mellitus (DM) susceptibility can elucidate disease mechanisms.
Objetivo del estudio:
- To investigate sex-specific genetic architectures of Alzheimer's disease (AD) and diabetes mellitus (DM) using genome-wide association studies (GWAS).; To identify sex-specific genetic loci and pleiotropic effects influencing susceptibility to AD and DM in European populations.; To explore the role of the APOE gene in sex-specific risks for AD and DM.
Principales métodos:
- Conducted genome-wide association studies (GWAS) and pleiotropic meta-analyses for AD and DM in European men and women.; Analyzed large cohorts: 172,097 men and 204,904 women for AD; 165,287 men and 195,190 women for DM.; Leveraged strong genetic associations with DM to identify weaker associations with AD, focusing on sex-specific effects.
Principales resultados:
- Identified 30 men-specific DM loci with pleiotropic effects on AD in gene clusters like THADA and IGF2BP2.; Discovered 16 women-specific DM loci with pleiotropic effects on AD in gene clusters including HNF1B and CDKN2B.; Female APOE ε4 carriers had higher AD risk (β=1.29) than males (β=1.12); APOE ε4 favorably associated with DM in both sexes without significant sex difference.
Conclusiones:
- Genetic susceptibility to DM and AD is more pronounced in men.; Antagonistic effects of APOE ε4 on AD and DM, along with sex-specific differences, underscore the importance of APOE-related genetic heterogeneity in AD-DM risk.; Sex-specific genetic factors play a critical role in the differential susceptibility to Alzheimer's disease and diabetes mellitus.
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