Blood Protein Analysis Reveals Menopause-Associated Signals of Brain Aging

Menopause affects women across midlife and is often accompanied by endocrine changes, hot flashes, brain fog and sleep disturbances. Women spend roughly one third of their lives after the menopause transition, yet links between this transition and later-life brain health remain incompletely understood. Blood-based biomarkers may help clarify biological changes that emerge before dementia is clinically apparent. 

Researchers at UC Santa Barbara, UC San Francisco, and collaborating international institutions identified a molecular signature involving 16 proteins associated with brain aging and dementia risk. Using advanced proteomic technologies, the team analyzed thousands of proteins in cohorts of pre-, peri-, and postmenopausal women from the Jacobs Lab’s Healthy Aging Study, which was established to examine brain and cognitive function in women and men during midlife.

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The protein changes involved inflammatory and neuronal processes, as well as pathways associated with Alzheimer’s disease. These shifts were more closely related to menopause stage than to chronological age, suggesting that menopause itself, rather than aging alone, was associated with the observed molecular changes. The findings were confirmed in a separate dataset of more than 2,800 women from the UK Biobank, which also showed menopause-related molecular signatures linked to accelerated aging across multiple organ systems.

The researchers then examined how these molecular changes related to brain health using data from four independent cohorts totaling nearly 12,000 older women. Women with higher levels of these risk-associated proteins were more likely to have poorer cognitive outcomes. In the largest cohort, the protein signature was also associated with a modestly increased risk of developing Alzheimer’s dementia over the following 16 years.

The findings were published in Nature Medicine. Collaborating institutions included UC Santa Barbara, UC San Francisco, Stanford University, the University of Toronto and Sunnybrook Research Institute. The team’s goal is to develop a blood test that could act as an early-warning sign of dementia risk, while the authors note that longitudinal studies following the same women through menopause will be essential to understand how hormones, proteins, symptoms and brain health change together over time.

“Menopause is not an isolated reproductive event. It is a whole-body biological transition. Now we can begin to see a molecular fingerprint of that transition in the blood and ask how it relates to brain health decades later,” said Emily Jacobs, a professor of psychological and brain sciences at UCSB.

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