Earlier menopause accelerates memory decline in women with APOE ε4 or inflammation, highlighting sex-specific Alzheimer’s disease risk factors.
Women are significantly more likely than men to develop Alzheimer’s disease, and earlier menopause has been linked to an increased risk for late-life cognitive decline. A new study presented at The Menopause Society’s 2025 Annual Meeting in Orlando found that this risk may be even greater in women who carry the APOE ε4 gene variant or who have systemic inflammation.1,2
Researchers from the University of Toronto, Sunnybrook Research Institute, and collaborating institutions conducted an analysis to determine whether the association between age at menopause and memory decline was modified by the APOE ε4 genotype or systemic inflammatory markers. The study used longitudinal data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study, including 2575 women without dementia at baseline.
Menopause history was self-reported, and APOE ε4 genotype was categorized as carrier versus noncarrier. Memory performance was measured annually using a composite score of episodic memory tests. In a subset of 257 participants, serum inflammatory markers were quantified using enzyme-linked immunosorbent assays. These included age-related inflammatory markers (interleukin-1β, tumor necrosis factor-α, and interleukin-6) and vascular inflammation markers (interleukin-6 receptor, matrix metallopeptidase-9, and vascular cell adhesion molecule).
Linear mixed models were used to test independent and interactive associations of age at menopause, APOE ε4 status, and inflammation on memory decline. Models adjusted for baseline age, years of education, menopause cause (spontaneous or surgical), hormone therapy use, baseline systolic blood pressure, baseline body mass index, and their interactions with time.
Participants had a mean age of 77.4 years and reported a mean age at menopause of 47 years, with 36% experiencing surgical menopause. Over an average follow-up of 8 years, earlier age at menopause was associated with faster memory decline (β = 0.038, P = .009).
A significant 3-way interaction was found between age at menopause, APOE ε4 status, and time. Women who carried the APOE ε4 variant showed stronger associations between earlier menopause and accelerated memory decline (β = 0.074, P = .009) compared with noncarriers.
Among the subset of women with available inflammatory data, higher levels of age-related inflammation further exacerbated the effect of earlier menopause on memory decline (β = 0.113, P = .03). Vascular inflammation did not significantly modify this relationship (β = 0.054, P = .29). Post hoc analyses indicated that the combined impact of inflammation and early menopause on memory decline was greater in APOE ε4 carriers than in noncarriers.
The study concluded that “the presence of APOE ε4 and age-related inflammation strengthened the link between earlier age at menopause and faster memory decline,” suggesting that these factors may be especially salient contributors to Alzheimer’s disease dementia risk in women who experience menopause earlier in life.
“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,” said Madeline Wood Alexander, lead author from the University of Toronto and Sunnybrook Research Institute. “Understanding how female biology influences Alzheimer’s disease risk is key to ensure we develop effective treatments for all individuals at risk.”
Stephanie Faubion, MD, MBA, medical director for The Menopause Society, emphasized the clinical importance of these findings, noting, “Given that women are at greater risk for Alzheimer’s 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.”
This study underscores the intersection of genetic, hormonal, and inflammatory factors in women’s brain health after menopause. The authors’ findings highlight the potential need for sex-specific strategies in Alzheimer’s disease research and treatment, particularly among women who experience earlier menopause and carry genetic risk variants such as APOE ε4.
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