Imagine designing a drug to treat female sexual dysfunction and then testing its side effects using mostly men. That actually happened a few years ago.
Until about 25 years ago, essentially all health research was conducted on men; women were actively excluded from participating in most clinical trials. Although researchers have been playing catch-up since then, this longtime bias put the health of women at risk and created a huge gap in knowledge about women’s health and the role that differences between women and men play in health and disease.
Alzheimer’s disease is a prime example of a condition for which we have little understanding of sex differences, other than that women bear the majority of the disease burden, both as patients and caregivers. About two-thirds of the 5.7 million Americans living with the disease are women, and about two-thirds of caregivers are women (even higher in Hispanic and African-American communities).
Why do so many more women have Alzheimer’s? The main reason is because women live longer than men and advanced age is the strongest risk factor for the disease. Growing evidence suggests that biological and sociocultural differences between women and men affect the development, progression, and treatment outcomes of Alzheimer’s disease. A better understanding of these differences can improve outcomes among both sexes.
To spur research in this area, experts affiliated with our organization, the Society for Women’s Health Research, published a review on Tuesday in the journal Alzheimer’s & Dementia. It outlines what we know — and what we don’t know — about sex differences in Alzheimer’s and makes recommendations for future research priorities.
Alzheimer’s is burdensome physically, emotionally, and economically for the individuals who have it, their caregivers, and society as a whole. This devastating disease is a top priority, as evidenced by the 126 ongoing clinical trials for new Alzheimer’s medications. Researchers are trying to find ways to intervene early enough to halt the progression of Alzheimer’s, and ultimately prevent it.
To do this, they need effective clinical trials. Understanding differences between women and men is an important part of that. For example, verbal memory tests are often used to diagnose Alzheimer’s disease. Women generally have better verbal memory than men. This advantage may help women maintain their cognitive function for longer than men in the early stages of Alzheimer’s, delaying diagnosis until the disease has progressed further. This could explain why women decline more rapidly after an Alzheimer’s diagnosis — it may be detected at a more advanced stage, limiting the opportunity for and impact of early intervention.
In research, biomarkers like beta amyloid, pathologic tau, and neurodegeneration are used to stage and measure the progression of Alzheimer’s disease. Identifying differences between women and men in these biomarkers and how they change across the lifespan is essential for clinical trial design. Yet much of this is still unknown because of the historic exclusion of women or lack of research that considers sex as a biological variable.
It’s also important to look at differences between women and men after data have been collected in clinical trials. Few clinical trials have examined sex differences in response to Alzheimer’s treatments, or the information has not been reported in the scientific literature. It is possible that analyzing data by sex will help improve the subtyping of Alzheimer’s disease and lead to better treatment options.
The exclusion of women in health research in the United States wasn’t just limited to clinical trials. It extended all the way to research on female animals, cells, and tissue. Why? Because of the persistent idea that female hormonal cycles were too difficult to manage in experiments — including the fear of harming potential pregnancies — and that using only one sex would reduce variation.
Fortunately, this has changed. In 1993, the National Institutes of Health Revitalization Act became law, mandating the inclusion of women and people of color in NIH-funded clinical trials. In the same year, the Food and Drug Administration changed its policies to require the inclusion of women in efficacy studies and in the analysis of data on sex differences. In 2016, the NIH implemented a new policy stating that sex as a biological variable should be factored into preclinical research and reporting in vertebrate animal and human studies.
Today, all federally funded researchers must either include both female and male research subjects or explain why they aren’t doing that.
Excluding women from clinical research has real harms: Of the 10 drugs pulled from the market between 1997 and 2000 because of unacceptable health risks, eight of them posed greater health risks to women. More recently, the FDA lowered the dosage of zolpidem, a drug used to treat insomnia, for women after reanalysis of data showed the drug was metabolized slower in women and could potentially cause harm, such as motor vehicle accidents the next morning.
It is also entirely possible that scientific breakthroughs have been overlooked because researchers were looking only at one sex or not analyzing data by sex. The first scientific breakthrough in lung cancer that affects individuals who never smoked, for example, was a genetic mutation in solid tumors commonly found in women of East Asian descent. That discovery led to the development of a medication that drastically shrinks these tumors and results in longer life for people with this mutation. Thanks to a close look at patients by sex, we now have a more sophisticated view of that cancer and available treatment options.
For almost 30 years, the Society for Women’s Health Research has worked to include more women in health and clinical research. We wish that sex parity was a long-established component of health research. Until it is, we will continue bringing together researchers, clinicians, and others with a stake in health research to identify knowledge gaps and ways to address them.
Amy M. Miller, Ph.D., is the president and CEO of the Society for Women’s Health Research. Rebecca Nebel, Ph.D., is the society’s director of scientific programs.