Public Release: 

Lower weight in late life may increase risk of Alzheimer's disease

BWH/MGH study associates lower body mass index with greater deposits of Alzheimer's-associated amyloid plaques in the brains of older individuals

Massachusetts General Hospital

Researchers at Brigham and Women's Hospital (BWH) and Massachusetts General Hospital (MGH) have found an association between lower weight and more extensive deposits of the Alzheimer's-associated protein beta-amyloid in the brains of cognitively normal older individuals. The association -- reported in the Journal of Alzheimer's Disease -- was seen in particular among individuals carrying the APOE4 gene variant, which is known to increase the risk of Alzheimer's.

"Elevated cortical amyloid is believed to be the first stage of the preclinical form of Alzheimer's disease, so our findings suggest that individuals who are underweight late in life may be at greater risk for this disease," says Gad Marshall, MD, of the MGH and BWH Departments of Neurology, senior author of the report. "Finding this association with a strong marker of Alzheimer's disease risk reinforces the idea that being underweight as you get older may not be a good thing when it comes to your brain health."

While the concept of a preclinical version of Alzheimer's disease is theoretical and not yet being used to guide clinical diagnosis or treatment, the current hypothesis involves three stages. Individuals at stage 1 are cognitively normal but have elevated amyloid deposits; stage 2 adds evidence of neurodegeneration, such as elevated tau deposits or characteristic loss of certain brain tissues, with no cognitive symptoms; and stage 3 adds cognitive changes that, while still in a normal range, indicate a decline for that individual. The current study is part of the MGH-based Harvard Aging Brain Study (HABS), designed to identify markers that predict who is likely to develop Alzheimer's disease and how soon symptoms are likely to develop.

This investigation explored the relationship between body mass index (BMI) and beta amyloid levels in the brains of the first 280 participants to enroll in HABS, who were ages 62 to 90, cognitively normal and in good general health. Participants' initial enrollment data included medical histories; physical exams; testing for the presence of APOE4, the major genetic risk factor for late-onset Alzheimer's; and PET imaging with Pittsburgh compound B (PiB), which can visualize amyloid plaques in the brain.

After adjusting for factors including age, sex, education and APOE4 status, researchers found that having a lower BMI was associated with greater retention of PiB, indicating more extensive amyloid deposits in the brain. The association was most pronounced in normal-weight participants, who were the group with the lowest BMI in the study. Analysis focused on APOE status revealed that the association between lower BMI and greater PiB retention was particularly significant for individuals with the APOE4 gene variant, which is associated with increased Alzheimer's disease risk.

Researchers hope that future studies will explain the mechanism behind the association between lower BMI and increased amyloid levels. "A likely explanation for the association is that low BMI is an indicator for frailty - a syndrome involving reduced weight, slower movement and loss of strength that is known to be associated with Alzheimer's risk," says Marshall, who is an assistant professor of Neurology at Harvard Medical School. "One way to get closer to determining any cause and effect relationship will be following these individuals over time to see whether their baseline BMI does predict the development of symptoms, which we are doing in HABS, and eventually investigating whether maintaining or even increasing BMI in late life has an effect on outcomes. Right now, we're also studying whether BMI is associated with any other clinical and imaging markers of Alzheimer's disease."

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David C. Hsu, MD, formerly with the MGH Department of Psychiatry and the BWH Department of Neurology and now at Mercy Medical Group in Sacramento, Calif., is lead author of the Journal of Alzheimer's Disease paper. This study was supported by the Harvard Aging Brain Study (NIH/NIA P01 AG036694, R01 AG037497, and R01 AG046396), K23 AG033634, K24 AG035007, and the Massachusetts Alzheimer's Disease Research Center (P50AG005134).

Brigham and Women's Hospital is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals.

Through investigation and discovery conducted at its Brigham Research Institute, BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit http://www.brighamandwomens.org/about_bwh/publicaffairs/default.aspx.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals." For more information visit http://www.massgeneral.org/news/default.aspx

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