Hormone therapy is widely used to treat menopausal symptoms such as hot flushes and night sweats. But scientists have long debated whether it affects dementia risk.
A new study adds another piece to this puzzle. It suggests that an Alzheimer’s biomarker may help identify which women are more vulnerable to dementia with certain hormone therapies.
Researchers analysed blood samples from 2,766 women recruited into a clinical trial in 1996 to 1999. They then followed participants until 2021 to examine whether levels of plasma p-tau217 at the start of the study were linked to people developing dementia, and whether this relationship differed depending on whether participants had used hormone therapy.
Plasma p-tau217 is a biomarker for Alzheimer’s disease, a measurable biological signal of the condition. Higher levels in the blood are linked to brain changes associated with Alzheimer’s.
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The study compared women who received a placebo or two types of hormone therapy. One was combined hormone therapy containing oestrogen and progesterone, usually prescribed for women who still have their womb. The other was oestrogen-only therapy, typically given after hysterectomy.
Women with higher levels of the Alzheimer’s biomarker had a substantially greater risk of developing dementia. In the study’s main analysis, higher baseline p-tau217 levels were associated with about three times the risk.
However, the relationship differed depending on the type of hormone therapy used. Among women assigned to combined hormone therapy, higher biomarker levels were linked to roughly four times the risk of dementia. This pattern was not seen among women using oestrogen-only therapy.
The association was strongest in certain groups, including women aged over 70, white women and those carrying the APOE4 genotype, a genetic variant that increases a person’s risk of developing Alzheimer’s disease.
Scientists think the difference between therapies may relate to how hormones interact with Alzheimer’s biology. Oestrogen may help protect brain cells and influence how the brain processes amyloid and tau proteins that accumulate in Alzheimer’s disease. Progesterone may modify these effects in ways that are not yet fully understood.
Colleagues and I earlier found that carriers of this genetic risk factor who used hormone therapy also had worse dementia-related biomarkers than those not using hormones or not carrying the genetic risk.
Earlier evidence
Data for the new analysis came from the Women’s Health Initiative studies, a large programme of clinical trials examining the long-term health effects of hormone therapy.
One component of this programme, the Women’s Health Initiative Memory Study, examined whether hormone therapy influenced dementia risk. The 2003 study found that combined hormone therapy roughly doubled the risk of dementia among women aged 65 and older. The wider hormone therapy trial was later stopped earlier than planned because overall risks, including breast cancer, stroke and blood clots, outweighed the benefits.
These findings applied to women who began hormone therapy after age 65. At the time, hormone therapy was often prescribed long-term to prevent conditions such as osteoporosis. Today it is usually started earlier, around menopause, which occurs at about age 50.
After these results were published, many women stopped taking hormone therapy, including those near menopause.
Later research suggested a more nuanced picture. Follow-up analyses of women who started hormone therapy between the ages of 50 and 54 found no evidence that treatment affected cognitive function when assessed six to seven years after the trial ended.
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Similar findings have been reported in other clinical trials of relatively healthy women who began hormone therapy close to menopause. These studies suggest that up to ten years of combined hormone therapy appears generally safe but does not provide measurable cognitive benefits.
The picture looks different when hormone therapy is started later in life.
Different results in older women
Among women who began hormone therapy after age 65 in the Women’s Health Initiative studies, overall cognitive performance declined when tested around age 70. This decline was particularly noticeable in women who already had lower cognitive function at the start of the study.
Further evidence came from a 2010 analysis of the same group of women. Eight years after joining the study, MRI scans showed trends towards smaller volumes in the hippocampus and frontal lobes among older women using combined hormone therapy.
Shrinking in the hippocampus is commonly seen in Alzheimer’s disease and may indicate that combined hormone therapy could worsen existing brain vulnerability in some older women.
New findings
The new analysis adds further evidence and is consistent with meta-analyses by my colleagues and me of national registry data showing increased Alzheimer’s risk in older women using combination hormone therapy but not oestrogen alone. A smaller increase was also seen in women nearer menopause when treatment lasted more than five years.
Menopausal symptoms themselves may also play a role. Severe hot flushes and night sweats have been linked to a higher risk of dementia when they occur later in life. Women with these symptoms are also more likely to use hormone therapy, making the effects of symptoms harder to separate from treatment.
Symptom severity is also associated with other dementia risk factors, including smoking and obesity, poor sleep, and stress and alcohol use.
What does this mean for women?
Importantly, this study does not show that hormone therapy itself causes dementia. Instead, it suggests that biological risk markers may help identify women who could be more vulnerable when treatment begins later in life.
Overall, the relationship between hormone therapy and dementia risk appears to depend on when treatment starts, whether someone already has underlying risk factors, and how long therapy is used.
Starting combined hormone therapy later in life, particularly after age 65, may increase the risk of cognitive decline in some women. But studies have generally not found the same risks when treatment begins around menopause and is used for shorter periods.
Taking hormone therapy for five years or less when started around menopause has not been linked to increased cognitive decline or Alzheimer’s disease in clinical trials or in most national registry studies.
Because most women use hormone therapy for a limited time to manage menopausal symptoms, it is unlikely to increase dementia risk when started around menopause.
