Sex-specific accelerated epigenetic aging in the Alzheimer's disease spectrum

BackgroundEpigenetic age acceleration (EAA) refers to the extent to which an individual's biological age, estimated from DNA methylation patterns, exceeds their chronological age, indicating accelerated cellular and tissue aging.ObjectiveWe investigated the association between EAA and Alzheimer's disease (AD), with a focus on sex-based differences.MethodsEAA was estimated from blood samples in 127 participants with Alzheimer's disease-related cognitive impairment (ADCI) and 143 cognitively unimpaired (CU) participants, recruited from a nationwide multicenter study under the Precision Medicine Platform for Mild Cognitive Impairment (PREMIER) consortium in Korea.ResultsEAA measures indicated higher acceleration in the ADCI group compared to the CU group, particularly for extrinsic epigenetic age acceleration (EEAA), AgeAccelResidualHannum, and AgeAccelPheno. Sex-specific analyses revealed that EEAA significantly differed between the ADCI and CU groups in both men and women, with a greater EEAA in men. Logistic regression analysis demonstrated that increased EEAA, the presence of <i>APOE</i> ɛ4 allele, and poorer nutritional status were significantly associated with a higher likelihood of ADCI. EEAA increased ADCI risk more strongly in men than in women, whereas chronological age showed a protective effect only in women.ConclusionsAs a marker of immune system aging, EEAA may be associated with ADCI. These findings suggest that EEAA serves as a complementary indicator of systemic biological aging within the AD spectrum. The greater EAA observed in men was consistently present in ADCI, highlighting the importance of considering sex differences in EAA-related AD research.