The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimer's disease spectrum

INTRODUCTION: Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging–mild cognitive impairment (MCI)–AD continuum and the mediating role of phosphorylated tau (p‐tau) versus other AD biomarkers. METHODS: Participants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin‐6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase‐3‐like protein 1. AD biomarkers were CSF p‐tau(181) and amyloid beta(1‐42) levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes. RESULTS: We found a sex‐by‐sTNFR2 interaction on Mini‐Mental State Examination and Clinical Dementia Rating‐Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p‐tau(181) eliminated the female‐specific relationships between neuroinflammation and cognition. DISCUSSION: Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.