In a cross-sectional cohort of 261 participants from the Cleveland Clinic Lou Ruvo Center Biobank, ten plasma inflammatory markers — including Flt-3L, MCP-1, soluble TREM2 (sTREM2), TNF, IL-8, IL-5, IL-12P40, IL-1RA, fractalkine, and G-CSF — showed inverse associations with the CSF pTau181/Aβ42 ratio, a validated index of Alzheimer's pathological burden. Plasma IL-5 was also inversely associated with clinical disease stage. Notably, associations between the pTau181/Aβ42 ratio and both MCP-1 and IL-12P40 were significant in females but not males, though these sex-interaction effects did not survive false discovery rate correction.
This preprint, not yet peer-reviewed, advances a growing body of evidence that peripheral immunity is not merely a bystander in Alzheimer's pathogenesis but may reflect or modulate central neuroinflammatory processes. The inverse directionality of these associations is biologically intriguing — lower circulating inflammatory signals correlating with worse AD pathology — potentially reflecting immune exhaustion or dysregulated peripheral-central immune crosstalk at advanced disease stages. The sTREM2 finding is particularly notable given TREM2's established role in microglial surveillance of amyloid. The emerging female-specific signal for MCP-1 and IL-12P40 aligns with known sex differences in immune aging and AD prevalence, though the failure to survive FDR correction demands caution. Critical limitations include the cross-sectional design precluding causal inference, the modest cohort of 261 participants, and reliance on Luminex multiplex platforms with variable sensitivity. Larger longitudinal studies stratified by sex are essential before these biomarkers can inform clinical staging or therapeutic targeting.