By 2050, around 135 million people^[1] worldwide will be living with dementia. The most common cause of dementia is Alzheimer’s disease. Women are more likely than men to develop Alzheimer’s disease, even after accounting for women living longer.

The symptoms of Alzheimer’s disease most commonly occur after the age of 65. However, changes in the brain begin decades before symptoms start. For women, this typically coincides with their transition to menopause.

Menopause results from the body decreasing production of two hormones made by the ovaries: oestrogen and progesterone. These hormonal changes are associated with a wide range of symptoms, including hot flushes, night sweats, difficulties sleeping, reduced libido, mood changes and brain fog.

Menopause hormonal therapy (also called hormone replacement therapy or HRT), including oestrogen alone or oestrogen combined with a progesterone, has been prescribed to help with menopausal symptoms for decades.

But how does menopause hormone therapy affect the risk of dementia? And why do some studies say the therapy increases the risk, while others say it reduces it?

Hormones and the brain

A large body of pre-clinical (animal based) research shows oestrogen helps protect the brain. It reduces any damage to nerve cells and supports overall brain health.

Receptors that respond to oestrogen are in areas of the brain related to reproductive functions. But they’re also in areas of the brain^[2] important for learning, memory and higher-order cognitive abilities such as planning, organisation and decision making.

Oestrogen protects the brain. RDNE Stock Project/Pexels^[3]

The loss of the “neuroprotective” effects of oestrogen after menopause is thought to contribute to more cases of Alzheimer’s disease in women than men.

Clinical studies^[4] have also shown women who have a medical or surgical menopause before the age of natural menopause have a higher lifelong risk of dementia and cognitive impairment.

This risk appears to be reduced^[5] in women who take oestrogen therapy after their surgery.

This has led researchers to hypothesise that adding oestrogen back – via menopause hormone therapy – might protect and maintain women’s cognitive health.

However, the research findings have not been consistent.

Could menopause hormone therapy impact dementia risk?

Concern about dementia risk and menopause hormone therapy have been partially driven by the unexpected findings from a landmark study conducted more than two decades ago.

The findings showed^[6] hormone therapy use in post-menopausal women, 65 years and older, was associated with an increased risk for dementia.

However, these studies have some key limitations:

1) most of the women were aged over 65 and more than ten years post-menopause

2) the type of oestrogen and progestogen (a synthetic form of progesterone) used may have less benefit on brain health.

The most recently published systematic review and meta-analysis^[7] of scientific data linking hormone therapy to the risk of Alzheimer’s disease included findings from 51 different reports that were published up to 2023.

The results showed if hormone therapy was initiated in midlife, or more generally within ten  years of the final menstrual period, there was a decreased risk of later-life Alzheimer’s disease compared to women not using any hormone therapy.

The greatest reduction in risk was associated with oestrogen-only hormone therapy.

In contrast, when considering using hormone therapy in late-life, or more than ten  years after menopause, oestrogen-only therapy had a neutral effects on Alzheimer’s disease risk.

However, oestrogen-progestogen therapy was associated with a risk increase.

Earlier studies had some important limitations. Mikhail Nilov/Pexels^[8]

Only one clinical trial^[9] has been published since this meta-analysis. This study examined the long-term effects of menopause hormone therapy use initiated in early menopause.

Women were on average aged 52.8 years and 1.5 years post-menopause when they entered this trial. They were randomly assigned to an oestrogen (with or without progestogen) or placebo for four years.

Researchers followed 275 women up ten years later. They found no cognitive effects (no harm nor any benefit) based on whether women were exposed to 48 months of hormone therapy or a placebo.

What affects your risk?

It appears the effects of menopause hormone therapy on dementia risk are influenced by several factors. These include when someone starts taking it, how long they take it for, the type of hormones used, and the person’s genetic and health background.

1. When therapy starts: the critical window hypothesis

One key factor in determining the effect of menopause hormone therapy on cognitive function and the risk of dementia appears to be when therapy starts relative to menopause. This is called the “critical window hypothesis”.

According to this hypothesis, oestrogen may help protect neurons in the brain only if started early in the menopause transition, particularly within a few years of menopause, when the brain may still be more responsive to hormones.

2. Type of menopause hormone therapy and the role of progesterone

The type of hormones included in hormone therapy can vary widely^[10] in their molecular structure as well as their physiological actions.

Different types of oestrogens (such as estradiol or conjugated oestrogen) and the inclusion of a progestogen (needed for women who have not undergone a hysterectomy) may have different impacts on brain health and dementia risk.

Some studies^[11] suggest adding a progestogen to oestrogen therapy could counteract some of the cognitive benefits of oestrogen alone, possibly by blocking oestrogen receptors in the brain.

Dementia risk is also dependent on a person’s genetic and health background. RDNE Stock Project/Pexels^[12]

3. The role of vasomotor symptoms

Vasomotor symptoms, such as hot flushes and night sweats, are the hallmark of menopause. Experiencing more vasomotor symptoms has been linked to poorer memory^[13] as well as an increase in biological markers^[14] associated with dementia risk.

Therefore, one possible pathway by which menopause hormone therapy may moderate Alzheimer’s disease risk is via their effects on reducing vasomotor symptoms.

4. An person’s genetic and health background

The greatest genetic risk factor for older-onset Alzheimer’s disease is carrying one or more copies of a specific version of the APOE gene, called APOE e4.

There is an emerging hypothesis^[15] that women who have this genetic risk for Alzheimer’s disease may show the greatest benefit from using hormone therapy.

What does this mean for you?

The clinical and scientific community are still debating whether menopause hormone therapy may play a role in Alzheimer’s disease risk.

Overall, the decision to use hormone therapy should be individualised, taking into account your age and timing of menopause, health status and specific menopause symptoms.

We need more research before we can make clear decisions about the role of hormone therapy and dementia risk, but based on the current evidence, hormone therapy may be beneficial if started early in the menopause transition, particularly for women at genetic risk of Alzheimer’s disease.

References

1. ^{^} around 135 million people (www.alzint.org)
2. ^{^} areas of the brain (pmc.ncbi.nlm.nih.gov)
3. ^{^} RDNE Stock Project/Pexels (www.pexels.com)
4. ^{^} Clinical studies (pubmed.ncbi.nlm.nih.gov)
5. ^{^} appears to be reduced (pubmed.ncbi.nlm.nih.gov)
6. ^{^} findings showed (jamanetwork.com)
7. ^{^} systematic review and meta-analysis (pmc.ncbi.nlm.nih.gov)
8. ^{^} Mikhail Nilov/Pexels (www.pexels.com)
9. ^{^} one clinical trial (journals.plos.org)
10. ^{^} vary widely (pmc.ncbi.nlm.nih.gov)
11. ^{^} Some studies (www.sciencedirect.com)
12. ^{^} RDNE Stock Project/Pexels (www.pexels.com)
13. ^{^} linked to poorer memory (journals.lww.com)
14. ^{^} increase in biological markers (pubmed.ncbi.nlm.nih.gov)
15. ^{^} emerging hypothesis (pubmed.ncbi.nlm.nih.gov)