Is a Big Belly Bad for the Brain? Examining Body Fat's Ties to Dementia

Belly fat may be bad for your brain. A number of recent studies, widely publicized in the media, have suggested that excess adipose tissue (body fat), particularly around the belly, during a person's midlife years may increase the risk of developing dementia, including Alzheimer's disease (AD), during old age. AD is the most common type of dementia among older people.

Just how adipose tissue and its many chemical components may affect the brain is a complex story that researchers are eagerly investigating, with support from the National Institute on Aging (NIA).

"We have two very serious public health burdens—Alzheimer's disease and obesity—and if they interact so that one accentuates the other, then this is obviously a significant crisis," says Dr. Suzana Petanceska, a program director in the NIA's Division of Neuroscience. "This is very important to know because if metabolic abnormalities associated with obesity do indeed harm the brain, and we are able to understand how that happens, there is great potential for intervention."

"Several epidemiological studies already show an association between body mass index (BMI) and dementia," says Dr. Lenore Launer, chief of NIA's Neuroepidemiology Section of the Laboratory of Epidemiology, Demography, and Biometry. (BMI is a measurement of body fat relative to height and weight.) In support of these findings, there are also "a lot of interesting new experimental data on proteins such as leptin that are involved in obesity and may indeed be involved in the physiology of brain changes," Dr. Launer says. "It's an exciting area that needs to be explored."

The epidemiological evidence

At first, researchers did not consider obesity to be an independent risk factor for dementia—separate from the conditions obesity spawns, including diabetes and cardiovascular disease. Numerous studies have linked both diabetes and cardiovascular disease to dementia. In the early 2000s, researchers turned their attention to obesity itself as an independent threat to the brain.

With support from NIA, Dr. Deborah Gustafson, Associate Professor, Neuropsychiatric Epidemiology Unit, University of Gothenburg, Sweden, and her colleagues analyzed data on dementia incidence in 290 Swedish women who were age 70 at the beginning of the study. Women who developed dementia in their 80s had an average BMI at age 70 that was 2 units (kg/m2) higher than that of women in their 80s who did not develop dementia. Imaging studies of women in another population study in Gothenburg showed that those with atrophy in their brains' temporal lobes were likely to have higher BMIs.

Since then, imaging studies have "convincingly demonstrated both generalized and regional brain atrophy and changes in white matter in association with obesity," writes Dr. William Jagust, a neurologist at the University of California, Berkeley, in the special issue on obesity and dementia of Current Alzheimer Research (April 2007).

Location, location, location

Research on the biology of fat has shown that there are several types of adipose tissue. Belly fat, also known as visceral fat, is the most damaging type. It wraps itself around organs, makes the abdomen protrude, and produces molecules that can pass into and interact with the brain. Compared with generalized obesity, excess visceral fat is a bigger risk factor for type 2 diabetes, insulin resistance, heart disease, stroke, and premature death, studies show. The fat that coats the hips and thighs, called subcutaneous fat, lies just below the skin and is benign in comparison.

In 2008, an NIA-funded study found that middle-aged people with large bellies are more likely than are their flat-bellied contemporaries to develop Alzheimer's later in life. Epidemiologist Dr. Rachel A. Whitmer, Kaiser Permanente Division of Research, Oakland, CA, and her co-investigators analyzed epidemiological data collected on 6,583 Kaiser members, ages 40 to 45. Almost 16 percent of the entire group developed dementia.

Study participants in the top third for belly size had a threefold greater risk of dementia than participants in the bottom third had, even after researchers controlled for other factors, like diabetes, that increase a person's risk for developing Alzheimer's. Some participants had a normal BMI and a large belly. They probably weighed less because they had little muscle in their arms and legs or had low bone density, Dr. Whitmer explains. But, they too were more likely than the flat-bellied participants were to develop dementia.

Effects of belly fat

"The more we understand about adipose tissue, the clearer it becomes that belly fat is its own disease-generating organism," says Dr. Launer. "Your fat is a very active endocrine organ that has a life of its own," Dr. Petanceska explains. As part of that life, it interacts with many other systems in the body. "How it interacts with the brain may profoundly inform us about brain aging and Alzheimer's," she adds.

We normally associate the changes that belly fat initiates with aging, so some researchers suggest that fat may accelerate the aging process. For example, visceral fat increases a person's risk of developing insulin resistance, to which older people are more prone than are younger people. Insulin resistance is a condition in which the body cannot use insulin properly. This condition typically leads to high levels of insulin in the blood, yet low levels of insulin activity in the brain. NIA-funded studies, including work by Dr. Suzanne Craft, VA Puget Sound Healthcare System and the University of Washington, Seattle, indicate a correlation between insulin resistance and the risk of age-related memory impairment and Alzheimer's disease.

Belly fat churns out a host of hormones, including cortisol and glucocorticoids known as stress hormones, which normally increase with age as well as during stress and are believed to affect cognition. The hippocampus, one of the main areas of the brain affected in AD, is rich in receptors for glucocorticoids. An elevated level of cortisol "has been linked to hippocampal atrophy in humans," writes Dr. Jagust.

The brains of AD patients show many signs of chronic inflammation. In addition, elevated levels of pro-inflammatory cytokines in the blood have been associated with a greater degree of age-related cognitive decline. Many of the substances produced by adipose tissue, known as adipokines, serve as mediators of inflammation (i.e., cytokines). The white adipose tissue that makes belly fat secretes cytokines that fuel and maintain a state of chronic inflammation, which is harmful to the body and may be one of the ways by which belly fat can accelerate brain aging and cause brain dysfunction.

Future research on obesity and dementia

Remaining questions

In an obesity and dementia special issue of Current Alzheimer Research, Dr. Petanceska posed the following questions that NIA is addressing or will address:

• Does metabolic syndrome (the combination of high triglycerides, cholesterol, blood pressure, blood sugars, and excess belly fat) alter normal brain aging and the transition from normal aging to AD? If so, how?
• Do the different conditions that make up metabolic syndrome interact to accelerate normal brain aging? If so, what are the mechanisms?
• How do obesity, hypertension, high blood cholesterol and triglycerides, and inflammation affect the brain's microvasculature, the dense and intricate web of small blood vessels that provides nutrients and oxygen to the brain and enables the proper functioning of neurons?
• Does being underfed or overfed as a baby and during childhood influence how the brain ages?
• Do stresses very early in life, or even before birth, affect a person's risk of developing late-onset AD? If so, do those stresses act indirectly on our DNA, altering the way our genes work?
• What is the effect of elevated stress hormones, such as glucocorticoids, as we age? Do they influence how metabolic changes in the body affect brain aging and the development of AD-related changes in the brain?
• If some of the conditions of metabolic syndrome contribute to development of AD, what should treatments target?

NIA-supported initiatives

Multidisciplinary workshop

In September 2008, the NIA convened a 2-day multidisciplinary workshop that brought together basic research scientists, epidemiologists, and clinicians from academia and the pharmaceutical industry, as well as representatives from other institutes within the NIH. The participants at this exploratory workshop critically appraised the current state of knowledge on obesity, metabolic syndrome, and cognition as it relates to AD. The workshop generated a number of new ideas as to how this complex subject can be addressed to advance our understanding and treatment of AD.

Other research directions

"What interests me is how changes in the brain's structure and function relate to the body's composition, such as levels of visceral and subcutaneous fat," says Dr. Launer. In 2002, she and colleagues began a large epidemiological study (the Age, Gene/Environment Susceptibility-Reykjavik Study) looking at that question.

"We are doing a lot of work in my lab using PET scans to measure how much amyloid, a major pathological hallmark of AD, is in the brain," Dr. Jagust says. "An important question is whether obesity intensifies the effect of amyloid or results in more amyloid being deposited. That's a question that I think someone will answer sooner or later with this imaging technology."

"To gain a better understanding of AD, we need to begin thinking 'outside of the brain,'" Dr. Petanceska writes in her editorial in Current Alzheimer Research, "so we can better understand the relationship between the health of the body and the health of the brain." Moving forward, she suggests, investigators also need to apply a lifespan research approach, because changes that occur early in childhood and even during prenatal development may trigger more changes leading to the late-life expression of AD.

Another avenue of research could look at whether excess weight leaves its mark after a person "quits," as smoking does, or whether losing the fat also removes the risk for AD.

"We are going to look at that question next," says Dr. Whitmer. Weight loss greatly lowers a person's risk of diabetes and other diseases, so it makes sense that it would reduce the risk of dementia, she says. The other good news is that visceral fat comes off first when people lose weight.