IL-17A levels in Alzheimer’s disease brains are mediated by X chromosome dosage

Among inflammatory mediators, interleukin-17A (IL-17A) has emerged as a potential contributor to AD pathogenesis, although its role remains incompletely defined. Notably, sex differences are evident in AD, with males exhibiting earlier mortality and greater cognitive deficits during aging and preclinical stages compared to females. While hormonal influences have been widely studied, the contribution of sex chromosome complement was suggested critical and remains poorly understood. Here, we investigated the impact of sex chromosome on cognitive function and neuroinflammation using amyloid and tau mouse models. Female Tg2576 and PS19 mice were crossed with XY* males to generate XX, XO, XY, and XXY genotypes, enabling separation of X from Y chromosomal effect. Behavioral assessments, including fear conditioning, novel object recognition, and Barnes maze, revealed that XY mice exhibited significantly greater cognitive impairment compared to XX and XXY counterparts. The same pattern was seen in IL-17A levels, indicating an effect of X chromosome instead of Y. Amyloid-β and phosphorylated tau pathology by immunohistochemistry and Elisa confirmed robust disease-associated accumulation in Tg2576 and PS19 mice, but showed no differences across sex chromosome complements. Collectively, our study identifies X chromosome dosage as a key modulator of cognitive resilience and IL-17A-linked neuroinflammation in AD models. Future studies focused on understanding how X-linked factors regulate IL17 mediated neuroinflammatory pathways could reveal novel therapeutic targets for AD.