Background: Alzheimer's disease (AD) disproportionately affects females with steeper cognitive decline and more neuropathology compared to males, which is exacerbated in females carrying the APOEɛ4 allele. The risk of developing AD is also higher in female APOEɛ4 carriers in earlier age groups (aged 65-75), and the progression from cognitively normal to mild cognitive impairment (MCI) and to AD may be influenced by sex. Inflammation is observed in AD and is related to aging, stress, and neuroplasticity, and although studies are scarce, sex differences are noted in inflammation.
Objective: The objective of this study was to investigate underlying physiological inflammatory mechanisms that may help explain why there are sex differences in AD and APOEɛ4 carriers.
Methods: We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOEɛ4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on CSF (N = 279) and plasma (N = 527) markers of stress and inflammation.
Results: We found CSF IL-16 and IL-8 levels differed by sex and APOE genotype, as IL-16 was higher in female APOEɛ4 carriers compared to non-carriers, while the opposite pattern was observed in males with IL-8. Furthermore, females had on average higher levels of plasma CRP and ICAM1 but lower levels of CSF ICAM1, IL-8, IL-16, and IgA than males. Carrying APOEɛ4 alleles and diagnosis (MCI and AD) decreased plasma CRP in both sexes.
Conclusion: Sex and APOE genotype differences in CSF and plasma inflammatory biomarkers support that the underlying physiological changes during aging differ by sex and tissue origin.
Keywords: APOEɛ4 alleles; CRP; IL-16; IL-8; Mild cognitive impairment; cortisol; cytokines; genotype; sex differences.