Does Midlife Obesity Increase Odds of Alzheimer’s Disease?

Claudia Satizabal will study the link between midlife obesity and Alzheimer’s disease. Photo by Cydney Scott

There is still no cure for Alzheimer’s disease; but scientists like Claudia Satizabal believe that it might be possible to prevent or delay some cases of Alzheimer’s by making healthy choices decades before symptoms surface.

Satizabal, an assistant professor of neurology at the Boston University School of Medicine (MED), wants to better understand how being obese in middle age affects your chances of developing Alzheimer’s later on. Some studies have already shown links between midlife obesity and dementia, but the evidence is confusing, and the nature of the biological links is still obscure. To illuminate them, Satizabal is looking to the records of the Framingham Heart Study (FHS), a treasure trove of data on more than 14,000 people collected over three generations and almost 70 years. Satizabal will spend the next two years studying the records of some 3,000 of those participants, trying to understand the relationship between obesity and Alzheimer’s. She hopes the research, supported by a $118K grant from the Alzheimer’s Association, will show how lifestyle choices can defend against the brain disease.

Obesity is bad for your heart and your blood vessels—that’s no surprise—and cardiovascular disease is also linked with cognitive decline and dementia. Yet studies looking for links between obesity in midlife and Alzheimer’s later on have produced mixed results. One reason is that people often start losing weight some years before they develop dementia, says Satizabal, and that phenomenon can confuse the search for links between obesity and Alzheimer’s.

“Midlife obesity may increase the risk of Alzheimer’s, but, in later life, maintaining body weight seems protective. It’s not a simple correlation,” says Sudha Seshadri, a MED professor of neurology and a senior investigator for the Framingham Heart Study, who works with Satizabal to study dementia with the FHS. So, to really understand the link between body weight and dementia, Satizabal wants to investigate a variety of markers of body and brain health collected decades before Alzheimer’s symptoms appear.

“As we start to understand this disease better and better, we know that it starts many years before the onset” of symptoms, she says. Once those symptoms become noticeable to patients and their families, the damage seems to be irreversible. That’s why Satizabal and other Alzheimer’s researchers are investigating early prevention and treatment, when the course of the disease can still be changed. “If you can predict who is at risk of developing the disease, you can target those populations and try to modify or delay the disease,” she says. “That’s really crucial.”

Most previous studies of Alzheimer’s and body weight have used body-mass index (BMI) as a proxy for obesity, says Satizabal. BMI is cheap and easy to measure—it’s just your weight divided by the square of your height—but it’s an imperfect stand-in for obesity. Muscle bulk can give an erroneously high BMI (going by BMI alone, Brad Pitt and Arnold Schwarzenegger qualify as obese), and there’s also evidence that the BMI scale isn’t properly calibrated for people of different races, genders, and ages.

Satizabal aims to do better by evaluating obesity in a variety of different ways, starting with relatively simple measurements, like waist circumference and waist-to-hip ratio, and advancing to scans that can identify whether fat is concentrated under the skin (subcutaneous fat) or around the organs (visceral fat), where researchers suspect it poses a greater health risk. She will also look at blood tests that can pick out specific biomarker molecules linked to obesity, all of which are already recorded in the Framingham data.

Some of these biomarkers are hormone-like chemicals called adipokines, which are produced by fat cells and direct the body to produce more or less of certain molecules. “There is a diverse range of adipokines,” says Seshadri. “Some are pro-inflammatory, some reduce inflammation, some have other direct functions on the brain.” None has yet been found to be responsible for the particular pattern of brain changes that is characteristic of Alzheimer’s, but Satizabal’s work may find a connection.

Satizabal will also look at biomarkers that come from fat in food. She suspects that, when it comes to staving off Alzheimer’s, the type of fat you eat may turn out to be more important than the total amount you consume. That is because some fats, like the trans fats that are now being removed from baked and fried snacks, ramp up inflammation, while others, like the omega-3 fats in fish, nuts, and seeds, tamp it down.

“Inflammation” has become a dirty word in pop-health headlines, but it’s actually a normal part of the body’s standard healing process. Inflammation becomes a problem only when it does not shut off. There is a growing consensus that perpetual, “low-grade” inflammation may be linked to a host of chronic illnesses—including Alzheimer’s.

“Although we don’t yet fully understand the exact mechanisms, evidence from several study lines point to the participation of inflammatory processes before, during, and after the onset of Alzheimer’s disease and other dementias,” says Satizabal. As part of her PhD work, she found that people with higher levels of inflammatory proteins circulating in their bodies were also likely to have brain shrinkage and blood vessel damage linked with Alzheimer’s. She hopes that her new research will show how choosing the right balance of fats in midlife could help keep the brain sharp decades later.

Satizabal will also study brain scans, taken during midlife, which may hold clues to how, and when, Alzheimer’s develops. She will be looking specifically at the size of the hippocampus, a part of the brain that helps make new memories, which tends to shrivel in people with Alzheimer’s. And because obesity and the diseases that go along with it, like diabetes and high blood pressure, damage the blood vessels that serve the brain, she will also be looking for signs that the brain’s white matter has been starved of oxygen and nutrients.

“This will tell us something about the biology through which obesity in midlife may be increasing risk of dementia, and it will tell us something about the impact of individual adipokines on the pattern of atrophy” as seen in the MRI scans, says Seshadri.

Because the Framingham Heart Study includes a rich collection of genetic data, Satizabal will also be able to examine how each study volunteer’s Alzheimer’s-related genes interact with obesity. One day, that could make it possible for doctors to give their patients genetically personalized diet recommendations.