By Franklin X. Faust
As published in Dimensions Magazine - Spring 2019
In 1965, a group of scientists serendipitously discovered that injecting aluminum salts into rabbits produced cognitive deficits and tangles in brain cells resembling those seen in human cases of Alzheimer’s disease. The finding mobilized the scientific community to investigate the connection between aluminum exposure and Alzheimer’s disease, spurring a new era of research. As word spread, many people became worried that everyday items they used in their homes could be putting their families at risk. But throughout decades of research, scientists failed to find a convincing link between aluminum exposure in humans and Alzheimer’s disease. Today, Alzheimer’s disease experts and researchers classify aluminum in household products as an unlikely risk factor and a dead-end in Alzheimer’s research. Even though the aluminum theory has been disputed and criticized for decades, a fear of aluminum still persists in public thought and on the labels of personal care products.
The years of aluminum research demonstrate that even the most popular scientific theories can be wrong. The scientific method is designed to produce the most accurate insights possible, but re-testing and peer review doesn’t happen overnight. “For a disease as serious and complex as Alzheimer’s, it’s understandable that people want answers and guidance sooner than scientific knowledge can progress,” says Dr. Paul Crane, MD, MPH, physician and researcher at UW Medicine. “Alzheimer’s disease research is a rapidly growing and changing field. If real scientific understanding is not distinguished from misleading, and often pseudoscientific claims, it can be nearly impossible for people to navigate on their own.”
Popularized books and articles reporting on science’s advancement often use phrases such as “Scientists have proven that…”, or, “Scientists have found this to be true…” People want simple, clear-cut answers, but a serious look at the scientific evidence behind some popular claims suggests that the truth is complicated. In an article recently published in JAMA, researchers in the Department of Neurology of University of California, San Francisco document a rise in false claims about supplements and ‘pseudomedicine’ for dementia and brain health. As more pseudomedicine makes its way into the public sphere, keeping a critical eye for “scientific” claims that extend past reliable scientific knowledge is particularly important. From gluten and carbohydrates, to coconut oil and the ketogenic diet, UW scientists can help us to set the record straight on their relevance to brain health and dementia risk.
Guidance on Gluten
A few years ago, the New York Times best-seller Grain Brain: The Surprising Truth about Wheat, Carbs, and Sugar – Your Brain’s Silent Killers cited Dr. Crane’s 2013 research published in the New England Journal of Medicine titled Glucose Levels and Risk of Dementia. Dr. Crane’s study found an association between higher levels of blood sugar and a higher risk of dementia, and the author pointed to Crane’s study to claim that gluten, sugar, and carbohydrate consumption increase dementia risk. The idea is that because gluten-heavy grains tend to have a higher glycemic index than fruits and vegetables, and therefore produce larger changes in blood sugar, eating more grains will increase your risk for dementia. But Crane does not view his study as evidence in support of these dietary claims.
Paul Crane, MD, MPH, UW Medicine
Blood sugar is different than dietary sugar - diet, genes, and exercise all interact to determine how a person’s blood sugar may spike after a big meal. “Normal Seattle diets were driving the differences in blood sugar we were seeing along with differences in genetics and other metabolic factors such as how much exercise people were getting,” says Dr. Crane. “Our study found an association between higher blood sugar and dementia risk. That’s not at all the same thing as finding that differences in gluten, sugar, or carbohydrate consumption were causing the association that we’d found.” The study was simply not designed to account for the differences in the diets of the participants. Claiming causation from association is a classic example of flawed logic, and any recommendation for intervention based on an associative, non-specific finding deserves significant scrutiny.
While it is generally likely that eating too much sugar and carbohydrates is unhealthy, and true that even people without celiac disease can have gluten sensitivities, evidence shows that cutting out all three completely is potentially dangerous for heart health. As suggested in a study published in 2017, people who adhere to gluten-free diets may consume fewer beneficial whole grains, which puts them at greater risk for cardiovascular disease. Not all claims, or grains for that matter, are created equal.
Coconut Oil, MCTs, and the Ketogenic Diet – A Need for Nuance
Coconut oil has been touted by some as a groundbreaking supplemental treatment for Alzheimer’s disease, but the scientific evidence suggests caution. For a miracle cure, coconut oil has a very high concentration of something most scientists and dietitians say people should try to avoid: saturated fat. According to Dr. Angela Hanson, MD, geriatrician and researcher at UW Medicine, “In general populations, high intake of saturated fat seems epidemiologically linked to increases in both Alzheimer’s disease and vascular dementia, and mouse models have given insight into some of the mechanisms behind those links.” A healthy heart promotes a healthy brain, and risk factors for cardiovascular disease also put one at greater risk for dementia.
A recent study by the American Heart Association found through randomized, controlled trials that a switch from saturated fat to unsaturated fat reduced cardiovascular disease by almost 30%, which is comparable with the risk reduction seen with statin treatment. Overall, the high concentration of saturated fat in coconut oil makes the claim for coconut oil as an effective Alzheimer’s disease supplement seem unconvincing. “There’s no clinical trials on coconut oil, and the evidence behind it is mixed,” says Dr. Hanson. “While using it every now and then is probably fine, I would be very cautious towards taking large doses of coconut oil for any reason.”
Angela Hanson, MD, UW Medicine, in the clinic
All that saturated fat begs the question - what is it about coconut oil that has some people claiming its potency as an Alzheimer’s disease treatment? In addition to its high concentration of saturated fat, coconut oil contains medium chain triglycerides (MCTs). MCTs are actually connected with the ‘ketogenic diet’, which is also touted as beneficial for the Alzheimer’s brain. The goal of the ketogenic diet, a diet very high in fat and low in carbohydrates, is to restrict carbohydrates to the point where the body switches into ketosis, a metabolic process usually triggered under starvation conditions. In ketosis, the liver converts fats into alternative fuel sources called ketone bodies. “These ketones seem to be able to enter the areas of the Alzheimer’s brain that can no longer access or utilize glucose for fuel,” says Dr. Hanson. “The idea is that more ketones to these brain regions will keep neurons fueled and promote better brain function.” While treating some neurological conditions with ketones or a ketogenic diet have shown beneficial effects, differences in outcomes between sub-populations highlight the need for a more nuanced view.
In fact, small clinical trials have suggested that MCTs are helpful for some patients with Alzheimer’s disease, but not others. Dr. Hanson’s own research suggests that the efficacy of the treatment may depend on a person’s genetics. “Carefully controlled ketone studies have not benefitted carriers of the APOE4 gene variant,” she says. “In one case, APOE4 carriers got worse in the short-term and may have actually been harmed by ketosis.”
The APOE4 gene variant is the strongest known genetic risk factor for developing Alzheimer’s disease after age 65, meaning that those who carry the APOE4 gene have been shown to be at a greater risk of developing the disease. Dr. Hanson has investigated the APOE4 effect on brain health outcomes from following a high-fat vs. low-fat diet. Her study found that APOE4 non-carriers had improved measures of cognition and reduced inflammation on the low-fat diet when compared to those on the high-fat diet, but that APOE4 carriers counter-intuitively performed better on the high-fat diet than on the low-fat diet. To Hanson, these findings shouldn’t be taken as dietary advice. “Most people don’t know their APOE4 status, so if people go on diets that are outside the norm, they could potentially be doing themselves more harm than good,” she says. “We have a lot to understand still, and as a person who studies personalized medicine, there may be different diets and treatments best for different groups.”
A ketogenic diet has other considerations that call its efficacy and implementation into question. Ketogenic diets have a long history of success in the treatment of neurological conditions; with studies first showing successful childhood epilepsy treatment in the 1920s. However, use of the diet to treat epilepsy in adults has been falling out of favor at UW Medicine. “Some UW Medicine physicians and dietitians have discontinued using the ketogenic diet for adults with seizures as they have not seen positive results,” says Anne Linge, a registered dietitian at UW Medicine. In her own practice, Linge also cautions against following low-carb diets for long periods, raising concerns that the lack of fruit, vegetables, and grains in the diet limit the microbiome’s food sources which could negatively impact the gut and brain alike.
Debra Clancy, a registered dietitian at UW Medicine, does not prescribe the diet and claims there are caveats to the potential benefits. “The ketogenic diet is a difficult diet for most people to follow. It can have lifestyle impacts as well as intolerable side-effects,” says Clancy. “It’s very important for people to consult with a dietitian before seriously engaging with such a diet.”
Evidence for Commonsense
Because there is no cure for Alzheimer’s disease, many people given a diagnosis of cognitive impairment tend towards pseudo-medicinal claims which seem to offer elements of hope. The marketing of “brain health” supplements is a huge industry, and it attracts a large audience by offering simple, pill-sized solutions to complex, frightening problems. But while many supplements claim universal cognitive benefits, they rarely have convincing evidence. A little-known fact is that supplements are not actually required to prove either safety or efficacy to the FDA before going on the market, so most supplements are only supported by limited research studies which lack strong certainty. A focus on these products and niche diets can divert resources away from lifestyle interventions that actually have strong evidence for benefitting cognition and brain health.
By Lenny Larsen, the Art of Alzheimer’s ‘Food for Thought’ exhibit. Art created at Elderwise.
There’s a better case for a balanced diet than for specific supplements and niche diets. “We’ve always been trying to find the magic pill for youth. I think a balanced diet with a variety of foods is going to be the right answer for most people’s long-term health,” says Dr. Hanson. “We’re talking about a diet that you can use to best improve your brain health over years. That diet has to be sustainable, livable, palpable to you and your culture and schedule.” Dr. Hanson, Linge, and Clancy all strongly recommend a Mediterranean diet, comprised highly of fruits and vegetables with a low intake of saturated fat and red meat, or a MIND diet, which emphasizes leafy green vegetables, berries, and nuts.
“The current research is strongly in favor of the Mediterranean or MIND diets as the best option for preventing cardiovascular disease and supporting healthy aging,” says Dr. Hanson. The research on these diets is not definitive, but a more complete picture is on the horizon. A randomized controlled trial is currently under way at Rush University to test the effects of MIND diet intervention on brain health, and it is projected to finish in April 2021.
A large body of evidence shows that an active lifestyle can be empowering in preventing and intervening in cases of progressive cognitive decline. According to the American Heart Association and American Stroke Association’s 2018 Presidential Advisory concerning Optimal Brain Health, a number of randomized, controlled exercise intervention trials have shown beneficial effects of exercise on cognition. Unlike many diet studies, these trials show clear, causal effects of exercise on improving brain health. And while APOE4 carriers are often thought to be more likely to develop Alzheimer’s disease, some studies have found that APOE4 carriers benefit even more from exercise. “It’s really encouraging because it challenges the notion that APOE4 carriers have worse disease and show signs earlier,” says Dr. Hanson. “These studies suggest that they have different metabolisms and routes that lead to Alzheimer’s disease, so different treatments might benefit them more or less.”
Overall, when thinking about brain health it is important to remember that an ounce of prevention is worth a pound of cure. While simple solutions are attractive and are unlikely to fall out of favor, evidence suggests that there will likely need to be a diversity of solutions for ensuring brain health and preventing or reversing cognitive decline. Researchers agree that precision medicine, not pseudomedicine, is the path to a healthier society. A one-size-fits all silver bullet for the prevention of neurodegenerative disease and dementia ignores the complexity involved in improving mental health outcomes. Instead, recognizing and studying the differences in development and trajectory of disease, and optimizing tailored treatments best for different groups will put us on the right path towards ensuring pro-active treatment and optimal brain health for all. •
Franklin X. Faust is a research scientist who works with the UW Integrated Brain Imaging Center to interpret neuroimaging data, in coordination with ADRC researchers. He is an intern on the ADRC communications team and helps with outreach.
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