Alzheimer’s Disease Affects More Women Than Men—and Some Experts Think The Reason Why Lies in the Gut

Alzheimer's disease—a progressive mental deterioration that can occur in middle or old age—is what experts call a complex medical condition. It isn't caused by one singular factor, like a caffeine-induced headache or a broken bone caused by an injury. Complex diseases involve multiple genes and environmental factors. In other words, it's complicated—very complicated, which has long hindered our understanding of the disease.

Further complicating matters is the fact that Alzheimer's disease affects upwards of 5 million Americanstwo-thirds of whom are women, per the Women's Alzheimer's Movement (WAM). While the disproportionate effect of Alzheimer's on women has long been known, scientists and doctors are only relatively recently starting to understand why. Answering the why just may change the course of action in terms of both prevention and treatment.

But what do you focus on when it comes to a disease that has myriad risk factors, including genes, hormones, diet, stress, and environmental factors? For some of the leading experts in Alzheimer's research, they're choosing to focus on the gut.

The Alzheimer's-Gut Connection

Alzheimer's is a deterioration of the brain, so it can be a little confusing to know why exactly the gut is taking center stage. As with seemingly everything else in health these days, it all comes down to the microbiome.

"The microbiome is all the bacteria, fungi, and viruses that live in the gut," says Laura Cox, PhD, an instructor at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School. (She received a grant from WAM in 2020 to fund her research.) It's important to have a high population of certain "good" bacteria strains and fungi in the gut. The good guys are linked to a variety of health benefits, including thriving brain health, while bad bacteria is linked to (amongst other health problems) deteriorating brain health.

Here's why: "What happens is that as we age, everything starts to break down. This is normal and natural, and we try to fight it," Dr. Cox says. This is called inflamm-aging, aka inflammation due to age. The gut barrier (which lines the inside of the gut and prevents harmful substances from being absorbed by the body) and the blood-brain barrier (the protective blood vessels surrounding the central nervous system) are included in this gradual systemic breakdown.

This is problematic for two reasons. One, these barriers become less able to block harmful microbes, pathogens, and other substances from circulating through your system. Second, since inflamm-aging impairs the immune system, the body is less able to kill harmful bacteria and pathogens that escape through the gut. "So you could have increased exposure to microbial products that are getting from the gut to the brain," Dr. Cox says. Both of these factors can lead to further bodily inflammationand experts believe that inflammation in the brain lays the groundwork for Alzheimer's. Given that the majority of your immune function happens in the gut—and that your microbiome supports said immune function as well as the integrity of the gut barrier—and you can see why researchers are interested in the relationship between the brain and the gut.

The Microbiome and Sex Differences in Alzheimer's Treatment

Hemraj Dodiya, PhD has been studying the differences between the microbiome-brain connection as it relates to Alzheimer's in women versus men for three years at the University of Chicago. He says that sex hormones and physiology in men and women affect the gut bacteria in the microbiome. The main question Dr. Dodiya and his team are working to answer is what bacteria strains in the gut are linked to amyloid deposits, which are buildups of plaque in the brain increasing the risk of Alzheimer's—and what strains are linked to reducing these deposits.

One study showed that a cocktail of five different antibiotics worked to reduce amyloid deposits in male mice, but not female mice. "We can attribute this to the male mice having a protective bacteria in the gut, while the female mice could potentially have a pro-inflammatory type of bacteria in the gut," Dr. Dodiya says. "Male and female mice have completely different reactions to antibiotic treatment that allows colonization or growth of certain bacterial species."

Dr. Dodiya says he's now exploring in several different experiments exploring how reproductive hormones interact with the bacteria in the gut and immune cells, in order to see if that explains the above-mentioned sex differences in the guts of mice. "[This communication] could then modulate what bacteria live and what bacteria die," he says. Future experiments could involve castrating male mice and studying how that changes their microbiomes in their set-up. In another experiment, testosterone supplements could be given to female mice to see how that affects their microbiome. "One experiment that I'm currently working on is taking presumably good bacteria from male [mice] and giving it to female mice," Dr. Dodiya says.

Dr. Cox has seen promise with female mice going a different route: reducing carbohydrate intake. "What was surprising about the study was that reducing carbs [to less than 30 percent of the overall diet] showed to be effective in reducing amyloid deposits in female mice, but not male mice," Dr. Cox says. Another surprise from the study is that the microbiomes of the female mice aged faster than the male's (meaning they started to break down sooner). But restricting carbs helped slow that aging process in the female mice, she says.

The Implications For Future Alzheimer's Treatment

All these mice experiments have some big takeaways for the future of Alzheimer's prevention and treatment, particularly in women. Dr. Dodiya says that he could see it leading to the development of probiotic supplements formulated to prevent Alzheimer's, with different stains for women than men. This is an outcome Dr. Cox says she could see too; designer probiotics that work as different drug therapies for men and women. But she emphasizes that more research needs to be done to pinpoint exactly what bacteria strains can cause Alzheimer's, as well as which strains could play a role in prevention. We're still several years off from that knowledge.

Another possible treatment method could lie in fecal transplants, pending how the experiment taking good bacteria from male mice and giving it to female mice turns out. (Yes, the idea of it may take some getting used to, but fecal transplants are already showing success when it comes to improving someone's microbiome.)

In terms of the carb reduction study, that's something Dr. Cox says women can consider putting into practice now with doctor supervision, though she emphasizes that the takeaway shouldn't be confused with reducing calories to an unhealthy level. After all, your brain needs sufficient vitamins and nutrients to function properly—and carbohydrates are the brain's preferred source of fuel. "Malnutrition in the elderly is already a problem, so it's important to be mindful of this," she says. It's more about eating fewer carbs and enough other beneficial macronutrients like protein, fat, and fiber.

What's clear is that while all of this research is promising, more needs to be done—especially on humans, not just mice. But what's encouraging is that researchers are really honing in on the differences between what causes Alzheimer's in men versus women, something that was long ignored. And addressing those differences lies a prevention plan that could be affective for everyone.

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