Inflammation and epigenetic age in Alzheimer's disease: do sex and APOE matter?

Alzheimer9s disease (AD) disproportionately affects females that carry the APOEϵ4 allele, and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be sex-specific. The objective of this study was to investigate underlying physiological inflammatory and epigenetic mechanisms that may help explain why there are sex differences in AD and APOEϵ4 carriers. Inflammation is observed in AD and is related to aging, stress and neuroplasticity, and aging biomarkers also include changes in DNA methylation patterns which have been used to determine epigenetic age. Although studies are scarce, sex differences are noted in inflammation and in epigenetic aging. We investigated using the ADNI database the effect of sex and APOE genotype (non-carriers or carriers of 1 or 2 APOEϵ4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF and plasma markers of stress and inflammation, and blood epigenetic age. We found sex and APOE genotype interactions on CSF levels of IL-8 and IL-16 cytokines suggesting that the presence of APOEϵ4 alleles differentially affects male and female physiology. Furthermore, females had higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males, showing in part that results may differ by sample source (plasma and CSF). Carrying 1 or 2 of APOEϵ4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes. Neither sex, diagnosis, nor presence of APOEϵ4 alleles affected epigenetic age acceleration. Sex differences in inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.