Alzheimer’s disease is not just a brain thief; it’s a gendered one. Of all people living with this form of dementia, two-thirds are women. They face a disproportionately higher risk of developing Alzheimer’s not simply because they typically outlive men but also because of intricate differences in brain biology. The gender disparity is woven into the very fabric of how the disease manifests and progresses, suggesting that Alzheimer’s isn’t a one-size-fits-all condition.
Initial studies point to a complex and sometimes conflicting web of contributing factors involving genes, hormones and inflammation. To better understand them, and to eventually give women the treatments they deserve, we need more basic research to unpack the mechanisms underlying these sex differences. Both estrogen and X-linked genes offer intriguing hints and a potential gold mine for future research.
Two hallmark proteins—amyloid beta, often referred to as “amyloid,” and tau tangles—define Alzheimer’s disease. The prevailing theory posits that amyloid is the gun, and tau is the bullet. As soon as amyloid hits a certain threshold, tau spreads like wildfire through the brain, sparking a slow but steady loss of memory and thinking abilities and eventually leading to an inability to function normally in daily life.
These proteins and their effect on memory show robust sex differences. Neuroimaging methods using radioactive “tracers” to visualize the proteins in the brain have consistently shown that amyloid levels are comparable between men and women. Where the story gets interesting, however, is that countless studies have now also shown that older women have much higher levels of tau than older men.
This tau abundance is particularly apparent in women who already have higher levels of amyloid in the brain, regardless of whether they are cognitively healthy or diagnosed with dementia. And these higher levels of tau result in much faster rates of memory loss over time in women than in men. The finding suggests that women may be more susceptible to the buildup of tau tangles, giving us some insight into how the disease might unfold differently for them. But it remains unclear what biological mechanism drives higher tau levels in women in the first place—and this is where basic science is desperately needed.
O
ne area of intense interest is the role of menopause and estrogen in Alzheimer’s disease. Estrogen has long been recognized for its broad biological protective effects, particularly in the brain. The abrupt decline in estrogen levels during menopause could contribute to increased Alzheimer’s risk in women. Those who have had both ovaries removed at earlier ages have poorer cognitive outcomes later in life. Treating ovariectomized mice with estrogen ameliorates cognitive symptoms, reduces depressive symptoms and improves heart health.Can menopausal hormone therapy reduce cognitive decline in women? The answer is complicated. In the late 1990s, one of the world’s largest randomized controlled trials to date, the Women’s Health Initiative, was launched to examine hormone therapy’s impact on women over the age of 65 years. Unfortunately, the trial was halted early because of increased risk on a range of different primary indicators, including stroke and cancer. The leaders of the trials also reported that women treated with hormone therapy had an almost two-fold increased risk of progression to dementia.
Later research, however, found that when people start hormone therapy is major factor in disease risk. Compelling evidence suggests that starting hormone therapy at least 15 years after menopause onset increases risk of a range of conditions, whereas initiating therapy around the time of symptom onset does not. It is not an understatement to say that the Women’s Health Initiative clinical trial set back the field of women’s health research by decades. National and international guidelines for hormone therapy recommend that women initiate treatment as close as possible to the onset of menopause symptoms.
So, is there any connection between tau and menopause or hormone therapy? Recent studies have found that postmenopausal women have higher levels of tau than men of a similar age. And earlier onset of menopause (younger than 40 to 45 years) may be associated with higher levels of tau, particularly if women already have higher levels of amyloid. Finally, a delayed start to hormone therapy treatment—one study estimates about 5 to 10 years after menopause—may be associated with particularly high risk for tau in the brain.
What does this all mean? At its simplest, it points to the importance of estrogen in Alzheimer’s risk. But we still don’t know why. We know that the brain has many estrogen receptors, and that estrogen is a potent hormone for a range of biological functions across the body. I hope we can reignite this area of exploration to really understand what mechanism might be helping to optimize or jeopardize women’s brain health.
T
he X chromosome offers another underexplored yet promising area of research in Alzheimer’s disease risk. Sex chromosomes have largely been ignored in genetics research for various technical reasons that have made it legitimately difficult to study them. But a recent large X-chromosome-wide association study (XWAS) identified some X-linked genes associated with Alzheimer’s risk, renewing interest. Another powerful study examined X-linked gene expression and Alzheimer’s disease pathology in the postmortem brain tissue of a large number of older adults. Of note, the researchers found quite a few genes that are protective against higher levels of amyloid and tau neuropathology, suggesting an avenue for biological resistance against disease. Interest in this area is only just heating up, and we have a long way to go.I want to end this story with a message of hope. Though its theme seems to be one of vulnerability for women, that couldn’t be further from the truth. One reason women are at greater risk of dementia is because they typically live significantly longer than men—and they also live longer with dementia. One of the most well-documented sex differences in aging research is that women outperform men on almost all cognitive tests. They outperform men so much that researchers are concerned that women are improperly diagnosed or underdiagnosed with dementia.
One of the quiet superpowers of the X chromosome is that women get two of them, one from each parent. If there is a mutation on the mother’s X, the father’s X can make up for it. To prevent potential overdosing from X expression in women, one X is randomly turned off in each cell across the body, resulting in a beautiful cellular mosaicism that men entirely lack. But not all X genes are silenced on that switched-off X chromosome, meaning that some genes do in fact become overdosed in women. A few labs are now hard at work trying to disentangle what this X inactivation escape might mean for Alzheimer’s disease risk. Some findings suggest these genes might be associated with immune responses and might increase both protection and risk. We’re just scratching the surface so far, with golden nuggets lying around just waiting for us to mine them for great discovery.
What else do we not know? So many things. There seems to be an intriguing link between sex and APOE4 genetic risk, but it’s unclear why. We have no idea what it means to initiate gender-affirming medicine early or late in life, or for that matter, to have XXY chromosomes, a condition known as Klinefelter syndrome. Sociocultural gendered factors, such as sex-biased access to educational and occupational opportunities, as well as differences in risk for mood disorders and modifiable lifestyle risk, including smoking, alcoholism and diet, may contribute. All will be important in understanding and treating Alzheimer’s disease in women and more broadly.
