Alzheimer's Biomarker May Identify Women Vulnerable to Dementia with Certain Hormone Therapies

Scientists have long debated the relationship between hormone therapy, used for menopausal symptoms, and dementia risk. A new study suggests that an Alzheimer’s biomarker, plasma p-tau217, may help identify women more vulnerable to dementia with certain hormone therapies.

Unpacking the New Research

Researchers analyzed blood samples from 2,766 women from a clinical trial conducted between 1996 and 1999. Participants were followed until 2021 to assess the link between initial plasma p-tau217 levels and dementia development, and whether this link varied with hormone therapy use. Plasma p-tau217 is a biomarker for Alzheimer's disease; higher levels are associated with brain changes indicative of the condition.

The study compared women receiving a placebo to those on two types of hormone therapy: combined hormone therapy (estrogen and progesterone), typically for women with a womb, and estrogen-only therapy, usually prescribed after a hysterectomy.

Key findings indicated that women with higher levels of the Alzheimer’s biomarker had a substantially greater risk of developing dementia, approximately three times higher. However, this relationship differed by the type of hormone therapy. Among women assigned to combined hormone therapy, higher biomarker levels were linked to roughly four times the risk of dementia. This pattern was not observed among women using estrogen-only therapy.

The association was most pronounced in specific groups, including women over 70, white women, and those carrying the APOE4 genotype, a genetic variant associated with increased Alzheimer's risk.

Researchers hypothesize that the difference between therapies may be due to how hormones interact with Alzheimer’s biology; estrogen might protect brain cells, while progesterone could modify these effects in ways not yet fully understood.

Reconsidering Past Findings: The WHI Legacy

Previous research, notably the Women’s Health Initiative (WHI) Memory Study (2003), found that combined hormone therapy roughly doubled dementia risk in women aged 65 and older. The broader WHI trial was halted early because overall risks, including breast cancer, stroke, and blood clots, outweighed benefits in this older age group. These findings primarily applied to women who started hormone therapy after age 65.

Subsequent analyses of women who began hormone therapy between ages 50 and 54 found no evidence that treatment affected cognitive function when assessed six to seven years after the trial concluded. Similar results from other clinical trials involving relatively healthy women starting hormone therapy close to menopause suggest that up to ten years of combined hormone therapy is generally safe but provides no measurable cognitive benefits.

In contrast, among WHI participants who started hormone therapy after age 65, overall cognitive performance declined around age 70, particularly in those who initially had lower cognitive function. A 2010 analysis showed trends toward smaller hippocampus and frontal lobe volumes in older women using combined hormone therapy, potentially indicating that it could worsen existing brain vulnerability in some older women.

Refining the Understanding: Duration, Timing, and Symptoms

The new analysis reinforces these findings and aligns with meta-analyses showing increased Alzheimer's risk in older women using combination hormone therapy, but not estrogen alone. A smaller increase was also noted in women closer to menopause if treatment lasted more than five years.

Menopausal symptoms themselves may also play a role. Severe hot flashes and night sweats occurring later in life have been linked to a higher risk of dementia. Women experiencing these symptoms are also more likely to use hormone therapy, complicating efforts to distinguish symptom effects from treatment effects. Symptom severity is also associated with other dementia risk factors, such as smoking, obesity, poor sleep, stress, and alcohol use.

Key Takeaways and Recommendations

This study does not conclude that hormone therapy directly causes dementia. Instead, it suggests that biological risk markers may help identify women who are more vulnerable when treatment begins later in life.

The relationship between hormone therapy and dementia risk appears to depend on when treatment starts, the presence of underlying risk factors, and the duration of therapy.

Starting combined hormone therapy later in life, especially after age 65, may increase the risk of cognitive decline in some women. However, studies have generally not found similar 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 most national registry studies. Therefore, for most women using hormone therapy for a limited time to manage menopausal symptoms, it is unlikely to increase dementia risk when started around menopause.