Research has established that women are twice as likely to develop Alzheimer’s. But, despite study after study into this sex-based disparity, scientists are still working to understand why. So far, research has shown that women have a few risk factors and warning signs that differ from men. Could these risk factors — like genes on the X chromosome and brain changes triggered by menopause — lead to a better understanding not only of this disparity, but of Alzheimer’s disease overall?

Sex differences haven’t always been front and center in medical research. Before a law was passed in 1993, it wasn’t even required  that  women be included in clinical trials. Even now, two out of three animal-based Alzheimer’s and dementia studies do not take sex as a biological variable into account. But, studying these important differences and getting to the bottom of why women are more vulnerable to Alzheimer’s can help scientists develop better treatments — for both women and men. 

1. The link between pregnancy and brain health 

One key biological difference Alzheimer’s researchers are probing is the impact of pregnancy on the brain.

High blood pressure during pregnancy — a common condition which will affect one in seven people — is linked to more cognitive decline and brain shrinkage down the line. Researchers believe this high blood pressure may damage blood vessels near the brain, and that can as much as triple the risk of developing Alzheimer’s or vascular dementia later in life.

2. Clues hidden in the X chromosome 

Most women carry two copies of the X chromosome, while most men only have one copy. This extra copy is normally dormant — it is there to serve as backup in case something goes wrong. However in some cases, genes from both copies of the X chromosome are produced. A few of these genes are even linked to cognitive aging and protein plaques and tangles in women, but not in men.

Scientists recently linked the production of one such X-linked gene called USP11 to increased levels of tau — a protein biomarker of Alzheimer’s — building up in the brain. Scientists have observed that too much USP11 can mean that cells that normally clean up the brain aren’t able to break down excesses of tau protein. Instead, these proteins get tangled up and start getting in the way of brain operations and even killing off brain cells.

3. Estrogen and menopause: Another piece of the puzzle

While estrogen is commonly known as a sex hormone, it also plays a role in brain signaling. In both men and women, estrogen appears to have neuroprotective properties that help the brain stay healthy longer. However, during menopause the levels of estrogen sharply decline, often leading to cognitive symptoms like brain fog. This drop in estrogen might also increase a person’s vulnerability to Alzheimer’s and other types of dementia. 

So, could increasing estrogen levels through hormone replacement therapy help women avoid these cognitive changes? So far, the research on HRT as a means of boosting post-menopause cognitive health and reducing dementia risk is inconclusive, but with more scientists on the case, we may know for sure in the coming years.