APOE ε4 and Inflammation Amplify Risk for Memory Decline in Women with Earlier Menopause

Women who experience menopause at an earlier age may face faster memory decline if they carry the APOE ε4 gene variant or exhibit higher levels of age-related inflammation, according to a new study presented this week at The Menopause Society’s 2025 Annual Meeting in Orlando. The findings highlight genetic and inflammatory factors as potential contributors to Alzheimer disease (AD) risk in women with earlier menopause.

Madeline Wood Alexander

Courtesy of University of Toronto

In a longitudinal analysis of 2,575 women without known dementia at baseline (mean age 77.4 ± 7.75 years; mean age at menopause 47.0 ± 6.86 years; 36% surgical menopause), researchers found that earlier menopause was independently associated with faster decline in episodic memory (β = 0.038, P  =.009). APOE ε4 carriers demonstrated a stronger association between earlier menopause and memory decline than non-carriers (β = 0.074, P =.009).

A subset of 257 participants with baseline inflammatory marker data revealed that higher age-related inflammation, measured via interleukin-1β, tumor necrosis factor-α, and interleukin-6, further exacerbated memory decline associated with earlier menopause (β = 0.113,P =.03). By contrast, markers of vascular inflammation, including interleukin-6 receptor, matrix metallopeptidase-9, and vascular cell adhesion molecule, did not significantly modify memory outcomes (β = 0.054, P =.29). Post hoc analyses suggested that inflammation’s effect on menopause-related memory decline was more pronounced in APOE ε4 carriers than in noncarriers.

Sex Differences Typically Overlooked

“Approximately 20% of Alzheimer’s therapeutics in development target genetic and inflammatory factors. Yet, sex differences and female-specific risk factors like menopause are often overlooked in clinical trials,” Madeline Wood Alexander, PhD, lead author from the University of Toronto and Sunnybrook Research Institute. “Understanding how female biology influences [Alzheimer] disease risk is key to ensure we develop effective treatments for all individuals at risk.”

Dr. Stephanie Faubion, medical director for The Menopause Society, emphasized the broader implications: “Given that women are at greater risk for [Alzheimer] disease than men, understanding the nuanced sex- and gender-specific mechanisms underlying these differences is essential for the development of targeted, individualized preventive and treatment strategies.”

The study pooled data from the Religious Orders Study, Rush Memory and Aging Project, and Minority Aging Research Study. Memory performance was quantified annually using a composite score of episodic memory tests, while APOE ε4 genotype was categorized as carrier versus non-carrier. Linear mixed models adjusted for baseline age, years of education, cause of menopause (spontaneous versus surgical), hormone therapy use, systolic blood pressure, and body mass index.

The findings suggest that APOE ε4 status and age-related inflammation may serve as salient modifiers of AD risk in women with earlier menopause, underscoring the need for sex-specific considerations in dementia research and the development of preventive strategies, Wood and colleagues concluded.

References

1. Alexander MW, Vandeloo KL, Splinter T, et al. Inflammation and APOE ε4 genotype modify the link between earlier menopause and memory decline. Abstract presented at: The Menopause Society’s 2025 Annual Meeting; October 21-25, 2025; Orlando, FL. Accessed October 21, 2025.

2. The role of genetics in modifying the link between earlier menopause and memory decline. News release. The Menopause Society. October 20, 2025. Accessed October 23, 2025. https://menopause.org/press-releases/the-role-of-genetics-in-modifying-the-link-between-earlier-menopause-and-memory-decline