09.02.2015
by Jeff Minerd
Contributing Writer, MedPage Today

Being obese or overweight at age 50 was associated with earlier onset of Alzheimer’s disease, according to a large prospective study from the National Institute on Aging (NIA).

Excess weight at middle age was also associated with more neurofibrillary tangles and amyloid deposits in the brain, two hallmarks of Alzheimer’s, reported senior investigator Madhav Thambisetty, MD, PhD, of the NIA in Baltimore, and colleagues, in Molecular Psychiatry.

Previous studies have reported a link between obesity at middle age and risk of Alzheimer’s disease, but they didn’t examine the specific relationship between obesity and age at onset of disease, Thambisetty told MedPage Today.

“There is a ‘whether’ component and a ‘when’ component, and the ‘when’ component has largely been ignored. Most studies haven’t followed a large enough group of people for long enough time,” he said.

Another novel aspect of the study was that it related obesity at middle age to Alzheimer’s pathology in the brain, he said.

Thambisetty and colleagues analyzed data from 1,394 participants in the Baltimore Longitudinal Study of Aging who were cognitively normal at baseline. These individuals were followed for an average of 14 years, but some as long as 35 years. They underwent cognitive testing every 1-2 years.

A total of 142 participants developed Alzheimer’s disease during the study. The investigators performed autopsies and neuropathological assessment on 191 participants and brain amyloid imaging on 75 participants.

After adjusting for sex, race, cardiovascular comorbidities, and other factors, the investigators found that each unit of increase in body-mass index (BMI) at midlife was associated with earlier onset of Alzheimer’s by 6.7 months (P=0.013).

Higher BMI in middle age also predicted neurofibrillary tangle burden in the brain as measured by the Braak score (P=0.0087).

The investigators found a trend toward higher BMI being associated with brain amyloid burden that did not reach statistical significance (P=0.075).

The scientists also examined the effect of the APOE4 gene variant, known to be involved in Alzheimer’s disease. APOE4-positive individuals had an earlier onset of Alzheimer’s by 3.4 years compared to APOE4-negative individuals, but the trend was not significant (P=0.11).

“Our findings clearly indicate that higher adiposity at midlife is associated with a long-lasting effect on accelerating the clinical course of Alzheimer’s disease,” the researchers concluded.

“From a public health perspective, the most relevant message here is that maintaining a healthy BMI as early as midlife could have a protective effect in terms of delaying Alzheimer’s disease decades later,” Thambisetty said.

Interventions aimed at middle age obesity could alter the trajectory of Alzheimer’s disease and reduce its public health burden, he added.

“It’s a compelling study, and it may give clinicians something else to help middle-aged patients understand how lifestyle and health choices will impact them years later,” saidSharon Brangman, MD, of the Upstate University Hospital in Syracuse, N.Y., and past president of the American Geriatrics Society.

“From a clinical standpoint, it makes the prevention and treatment of obesity important for physicians to address way before someone gets old,” Brangman told MedPage Today.

However, the study did not examine the effect of other factors associated with obesity that are known to affect the brain, such as diet, exercise, blood pressure, and blood sugar, Brangman noted.

For Wes Ashford, MD, PhD, of Stanford University in Palo Alto, Calif., the study raised as many questions as it answered. Ashford serves on the medical and scientific advisory board for the Alzheimer’s Foundation of America.

“It’s an interesting study, done by a good group of people. The results are solid. The question is what do they mean?” Ashford told MedPage Today.

Taken at face value, the study suggests that someone who drops his or her BMI by 10 points in middle age will delay the onset of disease by 5.5 years, Ashford said. “But are you really going to lengthen your life without dementia by five-and-a-half years, or is the damage already done? Should you have started to lose weight in your 20s?” he said.

In addition, “there’s a cause and effect problem here,” he said. “Is there something about being predisposed to Alzheimer’s disease that causes people to gain weight in the first place?”

Another puzzling aspect of the study is that people newly diagnosed with Alzheimer’s disease tend to weigh less than normal. “You rarely see Alzheimer’s patients who are overweight,” Ashford said.

It is also unclear whether patients in the study actually had Alzheimer’s disease or vascular dementia, Ashford said. The neurofibrillary tangles found in the autopsies are also highly related to vascular dementia, he noted.

Finally, although the study assessed patients’ APOE4 status, it didn’t distinguish between the six different APOE4 genotypes, some of which are much more strongly related to Alzheimer’s disease than others. “They talked about APOE4 status but not specific genotype, and that’s not adequate,” he said.

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

LAST UPDATED 09.02.2015