Hormone Replacement Therapy and Alzheimer Disease Risk: Is There a Link?

older couple with therapist
older couple with therapist
Researchers sought to assess the risks of developing dementia associated with different types and durations of menopausal hormone therapy, also known as hormone replacement therapy.

Use of menopausal hormone therapy, also known as hormone replacement therapy, in women, is not associated with an overall increased risk of developing dementia, according to study results published in the British Medical Journal (BMJ).

The researchers did note a slightly higher risk for Alzheimer disease (AD) among women who have taken estrogen-progesterone therapies for more than 5 years.

About 70% of the 80% of women who have menopause symptoms have symptoms that could be associated with future neurodegenerative decline. Prior research has produced varied findings on whether menopausal hormone therapy, also known as hormone replacement therapy, is associated with dementia. The objective of the current study was to further investigate the risks of developing dementia associated with the different types and durations of menopausal hormone therapy.

Researchers utilized a data sample from 2 large UK primary care databases: the Clinical Practice Research Datalink and QResearch. “It was designed with sufficient power not only to assess overall risk for women exposed to different types of long term hormone therapy but also to explore the differences between component hormones,” the researchers explained.

They conducted 2 nested case-control studies of data on women aged 55 years or older who had registered between January 1998 and July 2020. Women with dementia or dementia-related prescriptions before entering the study were excluded.

Researchers approximately age-matched patients diagnosed with dementia between 1998 and 2020 (118,501) to up to 5 controls (497,416). Only individuals with at least 10 years of medical records before the index date were included. First prescription for systemic estrogen was marked as start of exposure to hormone therapy, and prescriptions for hormone therapy issued in the 3 years before the index date were excluded. Exposure was defined as the sum of prescription periods.

Adjusting for confounders, no association existed between hormone therapy and risk for dementia for estrogen-only treatments (Adjusted Odds Ratio [AJR] 0.99 95% Confidence Interval [CI] 0.96 to 1.02) or estrogen-progesterone treatments (AJR 1.00 95% CI 0.97 to 1.03), for all hormone types.

In women younger than 80 years of age, exposure to estrogen-only treatment for more than 10 years was linked with a somewhat reduced risk for dementia (AJR 0.85 P =.003).

Exposure to estrogen-progesterone for more than 5 years was linked with increased risk for dementia (AJR 1.11 for 5 to 9 years 1.19 for at least 10 years, about 5 and 7 cases, respectively, per 10,000 woman years).

Study limitations included a possible lack of data before index date for some older women, indicate bias, and lack of data for some women for body mass index and cigarette and alcohol consumption.

“This study has shown that women taking oestrogen-only therapies are not at greater risk of developing Alzheimer’s disease and dementia overall, but that the risk of developing Alzheimer’s disease is increased among women with long term exposure of more than five years to oestrogen-progestogen therapies,” the researchers stated. “These associations do not prove any causal link, but risks of breast cancer are also associated with longer term hormone therapy use, so the results are in line with existing concerns in guidelines about long term exposures to combined hormone therapy treatments,” they concluded.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. Published online September 29, 2021. doi: 10.1136/bmj.n2182