Estrogen therapy linked to fewer signs of Alzheimer’s disease in brain tissue

Women who use estrogen-only hormone therapy during menopause may have a lower risk of developing the brain changes associated with Alzheimer’s disease. A large analysis of patient data found that those who used the therapy had less physical evidence of the disease in their brains and better memory test scores. The research was published in the journal Neurology.

Alzheimer’s disease disproportionately affects women, who make up more than two thirds of all patients worldwide. Researchers have investigated whether the natural decline of estrogen during menopause contributes to this disparity. Estrogen helps regulate physiological processes that keep the brain healthy, including inflammation and the integrity of the blood brain barrier. This barrier is a cellular filter that shields the brain from harmful substances in the bloodstream.

Past research on whether menopausal hormone therapy helps protect against dementia has yielded mixed results. Some trials suggested a protective effect, while others found either no benefit or an increased risk of cognitive decline. Variations in the timing of the treatment, the specific chemical formulation used, and the genetic backgrounds of the patients have made it difficult to draw a definitive conclusion.

To understand the relationship better, Stanford University psychiatry and behavioral sciences researcher Jennifer L. Bruno and colleagues examined records from thousands of older women. The research team wanted to see if they could link the use of estrogen-only hormone therapy to physical indicators of Alzheimer’s disease in the brain. They also looked at clinical diagnoses and memory test results.

The researchers analyzed information from two independent, large databases. The first was the National Alzheimer’s Coordinating Center, which collects data from dozens of research centers across the United States.

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The team focused on a specific group of female participants aged fifty and older. They separated these women into two categories: those who reported using estrogen-only menopausal hormone therapy and those who had never used it. Women who used a combination of estrogen and progestin were excluded from the main analysis.

Using this first database, Bruno and her team looked at autopsy records for 2,959 deceased women. Of these participants, 258 had used estrogen-only hormone therapy. The researchers compared the two groups based on a standardized scoring system that measures three distinct signs of Alzheimer’s disease in brain tissue. These signs include the buildup of amyloid proteins and the presence of tangled nerve fibers, both of which disrupt normal brain function.

The team found that women who had used estrogen-only hormone therapy had a measurably lower chance of exhibiting advanced Alzheimer’s disease pathology at the time of their death. The autopsies also revealed that these women had fewer signs of cerebrovascular disease, such as small strokes or damaged blood vessels in the brain. A secondary analysis of the autopsy data showed that the lower odds of brain pathology were specifically linked to a formulation called conjugated estrogens, rather than a different formulation known as estradiol.

Next, the researchers evaluated the clinical records of a large group of living patients from the same national database. This group included 1,841 hormone therapy users and 17,561 non-users. The researchers found that women in the hormone therapy group had lower odds of receiving a clinical dementia diagnosis. These women also showed fewer symptoms of general memory and functional decline compared to those who had not used the therapy.

To understand how hormone therapy might influence brain health while patients are still living, the researchers turned to a second database. The Alzheimer’s Disease Neuroimaging Initiative contains detailed biological measurements from living participants. From this dataset, the team identified 110 women who used estrogen-only hormone therapy and 1,948 who did not.

The researchers examined biological markers in the participants’ blood plasma and cerebrospinal fluid, which is the liquid that surrounds the brain and spinal cord. They measured the levels of amyloid proteins, which can clump together and form the plaques characteristic of Alzheimer’s disease.

Women who used the hormone therapy had higher levels of a specific amyloid protein, amyloid-beta 42, in their blood and spinal fluid. In these fluids, higher levels indicate that less amyloid is being deposited as plaques in the brain, so this pattern points to less Alzheimer’s-related amyloid buildup. Brain scans using a technology called positron emission tomography did not show a difference in amyloid accumulation between the two groups. The blood and fluid tests are generally more sensitive to early protein changes than the brain scans, suggesting that hormone therapy might be associated with lower levels of early stage amyloid buildup.

The team also reviewed cognitive test scores from the imaging database participants. They found that hormone therapy users scored higher on tests measuring immediate verbal memory and learning ability.

The researchers conducted exploratory analyses to see if genetics played a role. They separated the participants based on whether they carried the APOE e4 gene variant, which is a known risk factor for Alzheimer’s disease. The autopsy data showed that the hormone therapy was associated with less brain pathology only in women who did not carry this high-risk gene. The clinical benefits, such as a lower chance of a dementia diagnosis, were visible in both genetic groups.

Because this was an observational study, it cannot prove that the hormone therapy caused the improved brain health. It is possible that women who choose to take hormone therapy are generally healthier or have better access to healthcare to begin with. Unmeasured lifestyle factors could also contribute to the observed differences between the two groups.

The type of therapy examined in the study also limits how broadly the results apply. Estrogen-only hormone therapy is typically prescribed only to women who have had their uterus removed, because taking estrogen without progesterone can increase the risk of uterine cancer. Most women who undergo menopausal hormone therapy take a combined estrogen and progestogen regimen. The protective associations seen with estrogen alone might not extend to the combined treatments that are far more common in everyday medical practice.

The average age at which women in the study reported using hormone therapy was around seventy. Current medical guidelines usually recommend starting hormone therapy during the onset of menopause, typically in a woman’s late forties or early fifties, and stopping by age sixty. The researchers noted that a small subset of women in their data who started the therapy before age sixty also showed a lower chance of developing Alzheimer’s pathology, though the result was not statistically significant due to the small sample size.

Future research will need to follow patients over time in controlled trials to better evaluate how menopausal hormone therapy impacts physical markers of Alzheimer’s disease. Such studies could help medical professionals weigh the risks and benefits of prescribing the treatment to older women.

The study, “Association between menopausal hormone therapy and Alzheimer’s disease neuropathology,” was authored by Jennifer L. Bruno, Jacob S Shaw, and S.M. Hadi Hosseini.