Age at Menopause, Vascular Risk, and Cognition: A Review of Research

By: June Pauly

Editor’s Note: June is Alzheimer’s and Brain Awareness Month, a time to consider ways to improve and maintain cognitive function throughout one’s lifespan. This week’s research was summarized by June Pauly while on the FACTS fertility awareness elective for medical and other health professional students. The study by Wood et al is titled, “Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging.” [1] It was published in Neurology in 2024 and their findings are reviewed below.

Key Findings

Early-onset menopause and higher vascular risk were independently associated with lower cognitive scores
In combination, earlier menopause and increased vascular risk amplified the decrease in cognitive scores
Hormone therapy (HT) showed potential to attenuate the impact of early menopause and lower cognitive scores
The study [1] highlights the importance and consideration of reproductive hormones in slowing cognitive decline and dementia in women

Introduction

Women have a nearly two-fold higher risk of Alzheimer’s disease (AD) than men. Prior research suggests women also have more vascular risk factors and steeper cognitive decline than men. Hormonal changes, as during menopause, impact the development of AD; specifically, earlier menopause worsens AD pathology and cognitive decline.

“Women have a nearly two-fold higher risk of Alzheimer’s disease (AD) than men … (and) hormonal changes, as during menopause, impact the development of AD.”

It is intriguing to consider the potential interaction between the decline or loss of estrogen and alterations of other hormones affecting women’s cognition long term. Prior research suggests estrogen helps maintain and repair the endothelium of vessels, offering a degree of vascular protection. [2] Other studies reveal that estrogen is also neuroprotective because of its potential role in synaptic plasticity; it appears to delay both Alzheimer’s and Parkinson’s disease. [3][4] These data suggest a possible mechanism behind the link between estrogen and neurovascular protection.

“Studies reveal that estrogen is also neuroprotective because of its potential role in synaptic plasticity; it appears to delay both Alzheimer’s and Parkinson’s disease.”

Replacing hormones during menopause with hormone therapy could attenuate this cognitive decline. The study by Wood et al [1] investigated the relationship between age of menopause, vascular risk, and cognition.

Methods

Data were collected in the Canadian Longitudinal Study on Aging (CLSA) cohort at baseline and at 3-year follow up. Collected data included assigned sex at birth, gender identity, status and age of menopause. Lifetime use of hormone therapy was also reported along with the type and duration. Cognition tests were administered at baseline and at the 3-year follow up and included memory, language, and executive function tests. Menopause groups were split into: early menopause (ages 35–48), average menopause (ages 49–51), and late menopause (ages 52+). Vascular risk was quantified by a score of 0-6, with 1 point per risk factor: smoking, hypertension, treatment for hypertension, obesity, diabetes, and hypercholesterolemia. Data were analyzed with t tests, χ²tests, and linear regression models in R.

Results

The study included 8,360 postmenopausal women and an equal number of age-matched men. In women, early-onset menopause and a higher vascular risk score were significantly associated with lower cognitive scores. Additionally, the combination of earlier-onset menopause and increased vascular risk showed an amplified decline in cognitive scores. Although not significant, there was a trend that hormone therapy attenuated the effect of declined cognitive score in the early-onset menopause cohort.

“In women, early-onset menopause and a higher vascular risk score were significantly associated with lower cognitive scores.”

Discussion

It is crucial to understand why women experience greater cognitive decline and higher risk of Alzheimer’s disease than men. Dementia has a profound impact on patients and their loved ones and is highly prevalent in older populations. The early onset of menopause may intensify cognitive decline, especially when paired with vascular risk factors, which are already associated with worse outcomes. This is directly applicable to topics of women’s health when considering the risk factors for worse cognitive outcomes, as early menopause may exacerbate vascular risk factors. Awareness of this risk is important for women who may experience early menopause. More investigation is required to understand whether hormone therapy may offer these women some neuroprotection long term.

One of the strengths of this study is the large sample size of over 8,000 men and women. They used reliable, well-established methods to evaluate vascular risk and cognition. However, the age of menopause and history of prior use of hormone therapy were self-reported, which could result in recall bias. Additionally, the study included a predominantly Caucasian population from Canada with little diversity, limiting the generalizability of results. The study also evaluated associations between factors, and causal effects could not be drawn.

Clear differences exist in cognitive decline between women and men, and early menopause may be one of many factors causing or contributing to this discrepancy. Future research could explore how early menopause affects other body systems long term as well as the potential use of hormone therapy to attenuate cognitive decline.

The article by Wood et al highlights an immense knowledge gap in women’s health due to a lack of research. Reproductive hormones play a vital role in women’s health, impacting not only ovulation, fertility, and menopause but cognitive health as well. We need to explore the broader impact of these reproductive hormones through research to build a more individualized and equitable healthcare system.

“Reproductive hormones play a vital role in women’s health, impacting not only ovulation, fertility, and menopause but cognitive health as well.”

This study provides an opportunity to better understand how menopause affects a woman’s cognitive function. Future research should further investigate the causal relationship between early menopause and vascular risk and cognition with a more generalizable sample population that is multi-center. Follow-up duration longer than three years would also be beneficial given the insidious, long-term course a decline in cognition may take. The vascular risk factors women face should be addressed earlier, especially if there is a family history of early menopause, to prevent or delay future cognitive decline.

Editor’s Note: To learn more about this topic, follow the link to a research review written by medical student Gabrielle Riley while on the FACTS elective: Estrogen, Mitochondria, and their Impact on Brain Aging: A Review.

References

[1] Wood Alexander M, Wu CY, Coughlan GT, et al. Associations Between Age at Menopause, Vascular Risk, and 3-Year Cognitive Change in the Canadian Longitudinal Study on Aging. Neurology. 2024;102(9):e209298. doi:10.1212/WNL.0000000000209298

[2] Murphy E. Estrogen signaling and cardiovascular disease. Circ Res. 2011 Sep 2;109(6):687-96. doi: 10.1161/CIRCRESAHA.110.236687. PMID: 21885836; PMCID: PMC3398381.

[3] Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids. 2007 May;72(5):381-405. doi: 10.1016/j.steroids.2007.02.003. Epub 2007 Feb 21. PMID: 17379265; PMCID: PMC2048656.

[4] Phyllis M. Wise, Dena B. Dubal, Melinda E. Wilson, Shane W. Rau, Martina Böttner, Minireview: Neuroprotective Effects of Estrogen—New Insights into Mechanisms of Action, Endocrinology, Volume 142, Issue 3, 1 March 2001, Pages 969–973, https://doi.org/10.1210/endo.142.3.8033

ABOUT THE AUTHOR

June Pauly
June Pauly is a fourth-year medical student at Georgetown University School of Medicine in Washington, DC. She completed her undergraduate education at the California Polytechnic State University in San Luis Obispo, CA. She plans to pursue residency in neurology and is interested in health equity and education. She enrolled in the FACTS elective to gain a better understanding of natural family planning methods and ways to share these methods with patients to empower them in their health and reproductive decisions.

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