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

Background: Epigenetic 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. Objective: We investigated the association between EAA and Alzheimer's disease (AD), with a focus on sex-based differences. Methods: EAA 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. Results: EAA 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 APOE 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. Conclusions: As 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.