Sex-dependent role of inflammatory biomarkers in Alzheimer's disease-related cognitive performance

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Background Inflammatory factors are widely recognized as contributors to Alzheimer's disease (AD), along with pathological changes in amyloid-β (Aβ) and tau proteins. Objective We aimed to determine whether sex influences the inflammation-related cognitive performance. Methods This cross-sectional study included 317 patients (260 cognitively impaired and 57 cognitively normal) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) between September 7, 2005, and August 7, 2024. Interaction analysis was used to examine sex-specific effects of interleukins, while logistic regression examined associations between interleukins and clinically relevant worsening on non-memory Mini-Mental State Examination (MMSE) items (BCNMMMS). Linear regression assessed associations with hyperphosphorylated tau proteins (P-tau181). Finally, mediation analysis was conducted to investigate the role of sex hormone-binding globulin (SHBG) in interleukins, BCNMMMS, and P-tau181. Results In BCNMMMS, sex interactions were observed for IL-1β ( p = 0.048), IL-21 ( p = 0.020), and complement component 3 (C3) ( p = 0.041). After adjustment for confounding factors, IL-18 was associated with BCNMMMS in males (OR = 0.520 [0.274, 0.983]), while C3 was associated with BCNMMMS in females (OR = 0.452 [0.215, 0.950]). IL-21 and C3 levels were significantly associated with P-tau181 in females (IL-21: p = 0.002, C3: p = 0.047) but not in males. Besides, SHBG mediated the effect of IL-21 on cognitive performance in females (proportion of mediation = 19.72%; p = 0.032), suggesting a role for SHBG in sex-dependent inflammatory pathways related to cognitive performance. Conclusions Peripheral inflammatory biomarkers, particularly IL-21, showed sex-specific links to plasma P-tau181 and non-memory impairment in ADNI, supporting sex-stratified analyses.

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