Peripheral Indicators of Alzheimer's Disease Pathology in Women With Polycystic Ovary Syndrome: A Case-Control Study

Emerging evidence suggests that metabolic and hormonal disturbances in polycystic ovary syndrome (PCOS) may increase vulnerability to neurodegenerative disorders. However, the link between PCOS and Alzheimer's disease (AD)-related pathology remains unclear.

In this cross-sectional study, plasma levels of β-amyloid (Aβ₄₀, Aβ₄₂), phosphorylated tau (p-tau181), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified in women with PCOS and age-matched controls. Homeostasis model assessment of insulin resistance (HOMA-IR), inflammatory cytokines (IL-6, TNF-α) and hormonal parameters were assessed. Mediation and moderation analyses were conducted to explore metabolic and hormonal pathways underlying biomarker alterations.

Among 400 women (200 PCOS, 200 controls), age and BMI were comparable (P > 0.05). Compared with controls, PCOS participants had increased Aβ₄₀, p-tau181, NfL and GFAP, a slightly higher Aβ₄₂, and a lower Aβ₄₂/₄₀ ratio (all P < 0.05). p-tau181 correlated positively with HOMA-IR (r = 0.41) and IL-6 (r = 0.36), while Aβ₄₂/₄₀ ratio correlated negatively with HOMA-IR (r = -0.27). In multivariable analysis, p-tau181 (aOR = 1.34, 95% CI 1.05-1.71), IL-6 (aOR = 1.19) and TNF-α (aOR = 1.14) were independent predictors of insulin resistance. Mediation analysis indicated that HOMA-IR, IL-6 and TNF-α jointly mediated ∼ 71% of the PCOS-p-tau181 association, suggesting a metabolic-inflammatory pathway linking PCOS to AD-related tau pathology.

PCOS is linked to peripheral markers of early Alzheimer's pathology, largely mediated by insulin resistance and inflammation. PCOS may provide a clinical context to explore metabolic-inflammatory contributors to early neurodegenerative changes.