Inflammation in Alzheimer’s Disease: Do Sex and APOE Matter?

Article type: Research Article

Authors: Duarte-Guterman, Paula^a | Albert, Arianne Y.^b | Inkster, Amy M.^{c; d} | Barha, Cindy K.^e | Galea, Liisa A.M.^a | on behalf of the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Djavad Mowafaghian Centre for Brain Health and Department of Psychology, University of British Columbia, Vancouver, BC, Canada | [b] Women’s Health Research Institute of British Columbia, Vancouver, BC, Canada | [c] Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada | [d] BC Children’s Hospital Research Institute, Vancouver, BC, Canada | [e] Djavad Mowafaghian Centre for Brain Health and Department of Physical Therapy, University of British Columbia, Vancouver, BC, Canada

Correspondence: [*] Correspondence to: Liisa A.M. Galea, PhD, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada. E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: 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 APOE ɛ4 allele. The risk of developing AD is also higher in female APOE ɛ4 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 APOE ɛ4 carriers. Methods:We investigated, using the ADNI database, the effect of sex and APOE genotype (non-carriers or carriers of 1 and 2 APOE ɛ4 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 APOE ɛ4 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 APOE ɛ4 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: Mild cognitive impairment, APOEɛ4 alleles, genotype, cytokines, CRP, IL-16, IL-8, cortisol, sex differences

DOI: 10.3233/JAD-200982

Journal: Journal of Alzheimer's Disease, vol. 78, no. 2, pp. 627-641, 2020