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 (<i>N</i>>3,000) to identify biological changes underlying menopause and its links to brain aging. In <i>N</i>=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 (<i>N</i>=94; <i>N</i>=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 (<i>N</i>=2,814) replicated the observed proteomic shifts and revealed menopause-related upregulation of additional inflammatory and catabolic processes. The molecular signatures of menopause may inform biomarkers or therapeutic targets for brain health in women.
Authors
- Allesandra Iadipaolo
- Laura Pritschet (ORCID: https://orcid.org/0000-0003-4701-1017)
- Emily Goard Jacobs (ORCID: https://orcid.org/0000-0003-0001-5096)
- Michelle R. Caunca (ORCID: https://orcid.org/0000-0002-5177-9048)
- Madeline Wood Alexander (ORCID: https://orcid.org/0000-0003-4598-0201)
- Ramiro Eduardo Rea Reyes (ORCID: https://orcid.org/0000-0001-9749-282X)
- Marisa N. Denkinger (ORCID: https://orcid.org/0000-0002-3696-3795)
- Albert Pham
- Nina Miolane (ORCID: https://orcid.org/0000-0002-1200-9024)
- Rowan Saloner
- Matthew S Panizzon
- Jennifer S Rabin
- Emily W Paolillo
- Nicholas J Ashton
- Louisa Cornelis
- Valentina Diaz
- Kaitlin B Casaletto
- Joel Kramer
- Sterling C. Johnson
- Julia Borger
- Caitlin Taylor
Institutions
- Alzheimer's Association (US)
- Sunnybrook Health Science Centre (CA)
- University of Wisconsin–Madison (US)
- University of California, Santa Barbara (US)
- University of California, San Francisco (US)
- University of Toronto (CA)
- Toronto Rehabilitation Institute (CA)
- Banner Health (US)
- University of California San Diego (US)
- University Memory and Aging Center (US)
- Banner Sun Health Research Institute (US)
- Women's Health Initiative (US)
- Ontario Brain Institute (CA)
- University of Pennsylvania (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-02-11
- DOI
- https://doi.org/10.64898/2026.02.09.26345907
- Primary Topic
- Menopause: Health Impacts and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Association
- Larry L. Hillblom Foundation
- Alzheimer Society
- National Institutes of Health
- University of California, San Francisco
- Canadian Institutes of Health Research
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke