Of the more than 5 million Americans living with Alzheimer’s disease, nearly 2/3 of them are women. A woman in her 60s has a 1 in 6 chance of later developing Alzheimer’s, compared to only 1 in 11 for a man. What is the cause for this sex imbalance?

A major player in this question is the APOE gene (see The Genetics of Alzheimer’s Disease for more detail). This gene comes in three different forms: APOE2, APOE3, and APOE4. Each of us inherits two copies of this gene (one from each parent). If you have one copy of APOE4, your risk of Alzheimer’s increases threefold, while having two copies of APOE4 increases your risk by fifteen times. For reasons that remain unclear, the APOE4 allele seems to be a stronger risk factor for women than men, which could help to explain the difference in Alzheimer’s prevalence.

Some lines of research suggest that sex hormones may also play a role. Specifically, reduced estrogen levels, which commonly occur during menopause, are associated with increased risk of Alzheimer’s. Several studies have shown that women with Alzheimer’s tend to have lower estrogen levels in their brains. Pregnancy also reduces lifetime exposure to estrogen, which may explain why women who have had biological children have a higher risk of dementia than women without biological children. Similarly, women who have had a hysterectomy or oophorectomy (removal of the uterus or ovaries), which can induce menopause at an earlier age, also have an increased risk of dementia.

So if low estrogen is a risk factor for Alzheimer’s, could estrogen replacement therapy (ERT) combat this? ERT is commonly used as a treatment for menopausal symptoms such as hot flashes, as well as to reduce the risk of osteoperosis. Clinical trials investigating the effects of ERT on dementia have had mixed results. There is some evidence to suggest that it may only be protective if women begin treatment within the first few years of menopause. So far, the jury is still out on whether these therapies could be beneficial for preventing dementia. There are also some notable risks associated with ERT, including a higher chance of breast cancer.

What about male sex hormones? Similarly to women, men with Alzheimer’s disease tend to have lower levels of testosterone than normal. So if the loss of both sex hormones can increase the risk of Alzheimer’s, why do we see a much higher prevalence in women? One theory is that it relates to how quickly these hormones are lost. The menopause transition usually takes around four years, while male reproductive aging takes place gradually over several decades. Perhaps the abruptness of estrogen loss in menopause is responsible for the higher risk of dementia.

Another important difference between men and women lies in their risk for other dementia-related diseases. Women are more than twice as likely as men to have depression, and they also have a higher risk of insomnia and fragmented sleep. All of these conditions are linked to an increased risk of Alzheimer’s. In addition, women have historically been granted less access to education, employment, and physical exercise, which can be protective against dementia. This is particularly true for women who grew up in the mid-20th century and are now reaching their elderly years.

In conclusion, there’s still a lot we have to learn about why women are more prone to Alzheimer’s disease than men. In the meantime, both women and men can still greatly reduce their overall risk of Alzheimer’s through lifestyle changes. See 10 Tips to Reduce Your Dementia Risk to learn more.

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