Alzheimer's disease, which is characterized by cognitive decline and memory problems, is more common in women than men; currently two-thirds of the people with Alzheimer's in the U.S. are female, Healthline reports, even adjusted for age. Scientists are still trying to understand why this is, but research suggests that hormones — particularly estrogen — might play a role, both in protecting women from the damage of Alzheimer's and dementia, and in making them more vulnerable to it. If it sounds confusing, that's because the relationship between Alzheimer's and hormones is complicated.
Numerous studies have found that estrogen appears to help protect women's brains — up to a point. "The latest research, including my own work, indicates that estrogen serves to protect the female brain from aging," neurologist Dr. Lisa Mosconi wrote in The New York Times in 2018. "It stimulates neural activity and may help prevent the build up of plaques that are connected to the onset of Alzheimer’s disease." Estrogen affects the brain in many different ways; while we think of it primarily as a reproductive hormone, it's also involved in our neurological functions. And that means that it can help protect us from the factors that can cause Alzheimer's, at least for a while.
"Alzheimer's is characterised [sic] by a build-up of amyloid-β and tau proteins in the brain. Research has shown that oestrogen may help to protect the brain from Alzheimer's by blocking some of the harmful effects of the amyloid-β protein," explains the Alzheimer's Society. This blocking effect is still being understood, but research shows that estrogen in the brain can actually regulate levels of amyloid-β — and that helps keep us safe from its negative effects.
A big study published in 2018 found that the more estrogen a woman is exposed to over the course of her life, the less her risk of Alzheimer's and dementia. Women have spikes in estrogen levels when they have children, and in the study, women who'd had three or more kids were 12% less likely to develop dementia symptoms than those who'd only had one child. Women who'd had their first period relatively late — which meant less estrogen exposure over their lifetime — were also more likely to have Alzheimer's or dementia than women who had their periods early.
So how does estrogen actually make women more vulnerable to Alzheimer's? Women don't maintain the same estrogen levels throughout our lives. When we hit menopause, our estrogen levels dip naturally, and that becomes a problem. "When estrogen levels decline, the female brain becomes much more vulnerable," Dr. Mosconi wrote in the Times.
Menopause is the point when Alzheimer's risk in women may go up, and that appears to be directly tied to decreases in sex hormones. The loss of estrogen during aging, noted one study published in 2017, "is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders," and also might lead to the development of something called brain hypometabolism. Brain hypometabolism is a condition where the brain stops being able to metabolize glucose and fuel itself properly, and it's often seen in women with Alzheimer's — and plummeting estrogen might trigger it.
There's been a lot of disagreement about whether hormone replacement therapy (HRT) in women, which is designed to help deal with the consequences of menopause through artificial hormones, helps Alzheimer's risk or makes it worse. One 2019 study in Finland found it might increase Alzheimer's risk very slightly, but researchers told the BBC that the study was observational, meaning it didn't control for every factor, meaning other things might have influenced the increased risk. As of right now, scientists don't recommend that women avoid HRT altogether, but when you take it does appear to matter; having HRT between the ages of 50 and 54 shows no apparent effect, but having it between 65 and 79 may increase some symptoms of cognitive decline in some women.
When it comes to the sex differences behind Alzheimer's, other things besides estrogen are also to blame. A study in 2019 found that the tau proteins that build up in the brain in Alzheimer's tend to accumulate faster in women than in men, suggesting their illness gets worse more quickly. Genes also play a huge role; inheriting one of the APOE4 gene variants can increase your risk of Alzheimer's, and one variant causes risk to double in women while not having any effect on men. Alzheimer's can't just be pinned on hormonal shifts.
The hormonal story behind Alzheimer's is very complex, and there's still a lot to be learned about how estrogen and other hormones interact to help and hinder women's brains. More research needs to be done to thoroughly understand this link, and help women who may be at risk for Alzheimer's in the future.