Sex & Gender Differences in Alzheimer’s Prevention Research
by Women's Brain Health Initiative:
When she was a graduate student some decades ago, Dr. Margaret Fahnestock was told that scientific research involving female subjects was challenging. The rationale was that a woman’s hormonal cycle would ruin or interfere with the data in biochemical studies. That was then. Thankfully, attitudes have changed – albeit slowly – over time. Exploring sex and gender differences in the brain is now at the heart of her work on dementia, as part of a team supported by the Canadian Consortium on Neurodegeneration in Aging (CCNA).
Dr. Fahnestock, a Professor of Molecular Neuroscience at McMaster University, observed firsthand just how much things have changed when she attended a conference last year of the Organization for the Study of Sex Differences (OSSD) in Washington, DC. The OSSD was founded by scientists from the Society for Women’s Health Research, whose mission is to eliminate imbalances in health care for women.She listened to dozens of speakers discuss how researchers have focused for far too long on only male subjects, and how that, in turn, resulted in the scientific community not knowing as much as it should about women. “And this turns out to be really bad for medicine because there have been instances where women were given inappropriate treatments because they were prescribed drugs that we knew worked in males, but didn’t know if they worked at all that way in females.”
For Dr. Fahnestock, the OSSD conference was truly an eye-opener, as she heard many colleagues speak about their latest discoveries in a long-neglected field.
“I was absolutely amazed to hear that there are differences everywhere throughout the body in how males and females function, not just in the brain, but there have been no efforts until recently to study females at all. We’re missing half the population.”
Dr. Fahnestock’s graduate school teachings about the alleged challenges of studying female participants were thoroughly debunked. “Studying females is not nearly so difficult,” she said. In fact, she spends her days examining the brain molecules of both women and men, finding important differences.Her subgroup of researchers in the CCNA effort is working on the theme of prevention, with the goal of developing a greater understanding of the molecular and cellular basis of memory loss in diseases such as Alzheimer’s. Exploring the differences between women and men is central not only to her work, but also is a “cross-cutting” theme across CCNA projects, which means that while each team may be investigating different aspects of dementia, all are encouraged to include relevant considerations of sex and/or gender.
Both Women’s Brain Health Initiative (WBHI) and Brain Canada are providing funding for this aspect of the work, which carries the official title of the Women, Sex, Gender and Dementia (WSGD) Program.
Dr. Fahnestock and her colleagues are studying particular neurons in the brain that are necessary for learning and memory, which are the same neurons that degenerate and lose contact with each other in the early stages of Alzheimer’s disease. “My work is of a fundamental nature. A necessary precondition to finding a good way to prevent a disease is to understand it,” she said. Some of the most novel findings have come through examining a particular type of mice called “triple transgenic” or “3xTg”, whose brains mirror what is often found in humans with Alzheimer’s disease.
In particular, these mice possess amyloid beta plaques (deposits that appear as spots on images of the brain), as well as tangles within brain cells.Her colleague at McMaster University, neuroimmunologist Dr. Boris Sakic, noted that the 3xTg mice also have a severe autoimmune dysfunction. In autoimmune diseases, the immune system mistakenly attacks the body instead of protecting against harmful agents. Dr. Sakic observed that there was a notable difference between the male and female mice.
In particular, the female mice had a lower severity of the autoimmune disease, but a greater prevalence of plaques and tangles in the brain.
While the autoimmune dysfunction affected the males more significantly, with greatly enlarged spleens, they had fewer plaques and tangles.Dr. Sakic developed a hypothesis that autoimmunity could be protective – in other words, if the mice have more autoimmunity, they have fewer of the plaques and tangles associated with Alzheimer’s disease. But it was more complicated. Although the male mice had fewer plaques and tangles, they actually performed worse than the females on learning and memory tests.
“So we have a big puzzle with these mice to try to figure out what’s going on,” said Dr. Fahnestock. Her team is now running tests to try to determine whether it is autoimmunity that is causing the differences between female and male mouse brains or whether it is sex hormones.The findings speak to the evolving nature of Alzheimer’s research. For decades, scientists focused on plaques and tangles, developing drugs that could eliminate them in the hope that it could be a successful treatment option. However, clinical drug trials over the past few years have failed and the search for a cure remains elusive.
“That’s the short form of the history of why we’ve been so unsuccessful at curing Alzheimer’s disease,” Dr. Fahnestock explained. “It’s not really clear how plaques and tangles fit into the memory loss. They contribute for sure. But I’ve studied postmortem brains of people that have lots and lots of plaques, but when they died they were sharp as a tack. There was no memory loss at all.”
Researchers are now branching out and exploring other potential factors. Immune dysfunction is one of them, and Dr. Fahnestock’s team is using the male-female difference to try to develop a better understanding of how the immune system interacts with the brain. “So far, we’re coming up with more puzzles than answers. That’s not unusual. Research always leads to more questions. That’s why it’s such a fun field to be in. I’m never going to be out of business!”
Another CCNA research team within the prevention group, led by Guylaine Ferland, a Professor in the Department of Nutrition at the Université de Montréal, is exploring topics that are frequently discussed both within and outside of the scientific community: nutrition, exercise, and lifestyle.
“There is already much research indicating that diet can play a role in preserving brain health.”
There is now a Brain Health Food Guide, co-authored by Dr. Carol Greenwood and Dr. Matthew Parrott, that was unveiled in 2017 at Baycrest Health Sciences in Toronto. Inspired by the Mediterranean diet, the guide encourages the consumption of berries, leafy green vegetables, and nuts, while avoiding highly-processed meat and baked goods.
Dr. Ferland and her team have conducted an exhaustive survey of the existing literature and focused on a group of nearly 1,800 study volunteers from Quebec known as the NuAge (for nutrition and age) cohort. The NuAge group was comprised of healthy individuals between the ages of 67 and 84. Starting in 2003, the researchers tracked the participants for a number of years in order to gain a better understanding of the effects of nutrition and aging. Although the focus of the initial study was not cognition, Dr. Ferland’s team is mining the data in search of new insights, including a greater understanding of sex and gender differences.Her colleague, Dr. Alexandra Fiocco of Ryerson University, is in the final stages of preparing a research paper that analyzes sex, gender, nutrition, and cognition.
While Dr. Ferland noted that it is too early to speak publicly about the conclusions, Dr. Fiocco’s paper promises to be an important addition to our knowledge, because this is an understudied field. “There’s virtually nothing with respect to brain health and that’s what we plan to address as part of our team,” said Dr. Ferland.
They are currently in the process of recruiting a new group of study volunteers in Toronto for the next stage of their research. Titled LEAD (lifestyle, exercise, and diet), the project will focus on individuals between the ages of 60 and 85 who are experiencing at least two of three health challenges (namely, high blood pressure, high cholesterol, and diabetes), and who are noticing their memories are deteriorating.
The participants will be divided into two groups: one will be given general dietary advice and the other who will receive more specific information about the Brain Health diet. Every participant will be put on an exercise program. The researchers will examine the participants over a period of six months and will look not only for differences between the two test groups, but also between male and female subjects. “It’s something we will incorporate in our future analyses as much as possible because it’s really important from a public health view,” said Dr. Ferland.
Source: MIND OVER MATTER V10