Buck researchers weigh in on why women are more likely to develop Alzheimer’s disease

Women are more susceptible to Alzheimer’s disease. In March, a team from China published research in Nature.  finding that a hormone called follicle-stimulating hormone, or FSH, may play a key role in determining why. Tantalizingly, they also demonstrated that blocking FSH can reverse the process, leading to the speculation that a single drug that could block this hormone could treat not only Alzheimer’s disease, but a host of other maladies of aging, including obesity, osteoporosis and unhealthy blood lipid levels.

The research itself consisted of a number of experiments in mice, demonstrating that FSH acts directly on brain neurons. In mice that have a condition similar to human Alzheimer’s disease, FSH accelerated both decline in brain function and the anatomic signs of the disease (specifically, amyloid-β and Tau deposition in the brain). Blocking the hormone reduced the signs of damage. 

To make sense of this work, we turned to two Buck Institute researchers who study mechanisms of brain decline: assistant professors Tara Tracy, PhD and Jennifer Garrison, PhD.

Tara Tracy, PhD

“This is definitely the most extensive study of the effects of the female reproductive system on Alzheimer’s pathology,” says Tracy, who studies the molecular events that lead to synapse dysfunction and cognitive decline in Alzheimer’s disease. “For that reason, it has generated a lot of excitement in the Alzheimer’s research community.”

But is this terrifying news for women, who have no control over their hormone levels? Or just a scientific interest? Could a treatment be developed with this new insight?

Jennifer Garrison, PhD

“It is crazy how difficult it is to parse this information if you are not already in the field,"  says Garrison. A neuroscientist by training, she has pivoted in recent years to dive into the nuances of “reproductive aging,” co-founding and directing the Global Consortium for Reproductive Longevity & Equality.

A little background information about female hormones helps give the study perspective. As the female body ages, Garrison explains, it produces fewer sex hormones, most dramatically estrogen and progesterone. Previously, research has shown a link between early-onset menopause (between ages 40 and 45) and increased susceptibility to Alzheimer’s disease, but nobody knew why. 

This study highlighted the role of FSH. This hormone is produced in the pituitary gland and, in women of childbearing age, signals to their ovaries to stimulate the growth of eggs to maturity, with the levels peaking just before ovulation. It plays many other roles, including with body fat, bone mass and serum cholesterol. In men, FSH helps control sperm production.

In the simplest terms, during perimenopause and menopause, estrogen levels drop, and its ability to turn down FSH production is diminished or absent. FSH levels “are all over the map” leading up to menopause, says Garrison, and can go very high during menopause.

FSH is one player in a huge, intricate hormonal cycle in women, which includes estrogen, progesterone and FSH, among others. “There are a lot of things going on,” says Garrison. “Female reproductive biology is one of the most complex signatures in human health.” 

To further complicate understanding of why women are more susceptible to Alzheimer’s disease, what is known as “Alzheimer’s disease” might be multiple different conditions that are lumped together as one disease because nobody knows yet how to differentiate them, she says. 

As a step in cutting through some of the complexity, “this study shows a really interesting novel link,” says Tracy, connecting the effect of the ovaries and FSH with pathology in the brain, and to what extent cognition is affected. 

Tracy points out that the research team went beyond simply showing physical changes in the brain, they also demonstrated changes that either improved the behavioral performance or memory of the mice or made it worse, depending on FSH levels. “A nice thing about this paper was that they showed not only that they could make the system worse but they can recover some function,” she says.

However, as is true about all studies done in mice, she cautions people to not read too much into this. The work was done in a very well established mouse model, which is enormously useful in some ways, but limited in its ability to mimic human Alzheimer’s disease. Additionally, mice have such short lifespans, it is hard to compare how long it would take for such an effect to take place in humans. 

Caveats aside, this is big news. 

“It’s exciting because it opens up a whole series of hypotheses that we can now test,” says Garrison. “It’s a really great promising early study, and there are just so many questions that arise from it that I can imagine some really cool work to address them,” including looking at FSH’s role in metabolism, bone loss and other markers of ovarian aging.

“We know that there are greater risk factors for women, and we need to keep working on this angle,” says Tracy. “This study is highlighting what is to come.”

Xiong, J., et al. (2022) FSH blockade improves cognition in mice with Alzheimer’s disease. Nature doi.org/10.1038/s41586-022-04463-0