Blood-based proteomic signatures of spontaneous menopause: Implications for later-life brain aging and Alzheimer’s disease risk

Menopause is a hallmark process in biological aging that has been associated with later life neurodegenerative risk. We leveraged proteomics data from multiple cohorts (N>3,000) to identify biological changes underlying menopause and its links to brain aging. In N=80 rigorously-phenotyped pre-, peri-, and postmenopausal women with serum NULISAseq proteomics, spontaneous menopause was characterized by dysregulation in inflammatory, synaptic, metabolic, and Alzheimer’s disease (AD) biologic processes, which tracked with hormones and not age. Pro-inflammatory protein upregulation was especially pronounced in women with vasomotor symptoms. In two cohorts of older women (N=94; N=100), menopause-related proteomic elevations associated with poorer cognitive outcomes and plasma AD biomarkers. Finally, validation analyses in age-matched pre- and postmenopausal women with plasma Olink proteomics (N=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and hormone signaling processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.