Blood proteomics of menopause map to brain aging and dementia risk
Abstract
Abstract Menopause is a hallmark process in biological aging that has been implicated in later neurodegenerative risk, but the pathways underlying this connection remain unclear. Here we used blood proteomics data from several cohorts to identify biological changes associated with menopause and its links to brain aging. In n = 80 rigorously staged (STRAW+10) pre-, peri- and postmenopausal women (aged 43–58 years) with serum NULISAseq proteomics, we show that spontaneous menopause is characterized by dysregulation in inflammatory, synaptic, metabolic and Alzheimer’s disease biologic processes, which tracked more strongly with hormones than with age. Validation analyses in age-matched pre-/peri- and postmenopausal women ( n = 2,814) with plasma Olink proteomics replicated the observed proteomic shifts and revealed broader menopause-related upregulation of inflammatory and catabolic processes plus accelerated organ and cell aging, including brain aging. In four independent cohorts of older women (average age, 60.7–72.1 years; total n = 11,925), higher menopause proteomic scores associated consistently with cognitive aging and dementia risk. The molecular signatures of menopause may inform the selection of biomarkers or therapeutic targets for brain health in midlife women.
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Authors: Madeline Wood Alexander, Jennifer S. Rabin, Michelle Caunca, Allesandra Iadipaolo, Louisa Cornelis, Ria Warrier, Keenan A. Walker, Nina Miolane, Veronica Augustina Bot, Brendan Wood, Hamilton Se‐Hwee Oh, Tony Wyss‐Coray, Albert Pham, Julia Borger, Valentina Diaz, Emily W. Paolillo, Joel Kramer, Laura Pritschet, Caitlin Taylor, Matthew S. Panizzon, Ramiro Eduardo Rea Reyes, Marisa N. Denkinger, Nicholas J. Ashton, Sterling C. Johnson, Emily Goard Jacobs, Rowan Saloner, Kaitlin Blackstone Casaletto
Institutions: University of California, Santa Barbara, University of Pennsylvania, Icahn School of Medicine at Mount Sinai, University of California San Diego, University of California, San Francisco, University of Toronto, Stanford University, University of Wisconsin–Madison, Allen Institute for Brain Science, Sunnybrook Health Science Centre, Sunnybrook Research Institute, Health Sciences Centre, Toronto Rehabilitation Institute, National Institute on Aging, Banner Sun Health Research Institute, Neurosciences Institute, Harquail Centre for Neuromodulation, Banner Alzheimer’s Institute