Sexual dimorphisms in innate immune activation markers in predementia Alzheimer's disease

Females have an increased risk of developing Alzheimer's disease (AD). The innate immune system plays a key role in AD pathology, and sex differences in innate immune responses may contribute to differences in disease risk and progression. This study investigated sex differences in innate immune responses among participants without cerebrospinal fluid (CSF) determined amyloid pathology [A-; cognitively normal (CN), n = 83] and those with amyloid pathology (A+, n = 202), further stratified into preclinical (CN with A+, n = 72) and mild cognitive impairment (MCI with A+, n = 130). Participants were drawn from the Norwegian Dementia Disease Initiation cohort (n = 285). We measured plasma glial fibrillary acidic protein (GFAP) and CSF concentrations of nine innate immune markers: soluble triggering receptor expressed on myeloid cells 2 (sTREM2), monocyte chemoattractant protein 1 (MCP-1), fractalkine, chitinase 3-like 1 (YKL-40), clusterin, interferon gamma (IFN-γ), interleukin-6 (IL-6), IL-10, and IL-18. Linear regression was used, adjusted for multiple comparisons using the false discovery rate. In A+ cases (n = 202, females = 105), females had lower MCP-1 (P  < 0.01), IL-6 and IL-18 (both P  < 0.05) than males, while no sex differences were observed in A- cases (n = 83, females = 39). Among A+ participants, no sex differences were observed in CN cases (n = 72, females = 37), but females (n = 68) with MCI had lower MCP-1 and IL-6 (both P  < 0.05) than males (n = 62) with MCI. Moreover, A+ females exhibited stronger positive associations between sTREM2 and clusterin with CSF total tau (P < 0.001; P < 0.05) and Neurofilament light chain (P < 0.01; P < 0.01) than males. These findings suggest sex-specific differences in innate immune responses, which may contribute to disease progression in amyloid-positive individuals.