Summary: A study from Brigham and Women’s Hospital and Massachusetts General Hospital links lower late-life BMI with higher cortical amyloid deposits, particularly among carriers of the APOE4 gene.
Source: Mass General.
Lower body mass index in older adults is associated with greater Alzheimer’s-related amyloid accumulation
Researchers at Brigham and Women’s Hospital (BWH) and Massachusetts General Hospital (MGH) report that cognitively normal older adults with lower body mass index (BMI) show greater deposits of beta-amyloid in the brain, a hallmark of Alzheimer’s disease. The association was strongest among individuals who carry the APOE4 gene variant, a well-established genetic risk factor for late-onset Alzheimer’s disease. The findings appear in the Journal of Alzheimer’s Disease.
Elevated cortical amyloid is widely regarded as an early indicator of preclinical Alzheimer’s disease. In this study, the investigators suggest that low BMI late in life could be a marker of increased risk for amyloid accumulation, and therefore potentially for subsequent neurodegeneration. Gad Marshall, MD (MGH and BWH Departments of Neurology) and senior author of the report, notes that low weight in older age may reflect frailty and other processes that correlate with Alzheimer’s risk.
The analysis used baseline data from the first 280 participants enrolled in the Harvard Aging Brain Study (HABS). All participants were community-dwelling, cognitively normal men and women aged 62 to 90 and in generally good health. Enrollment assessments included medical history, physical examination, APOE genotyping, and PET imaging with Pittsburgh compound B (PiB) to visualize cortical amyloid plaque burden.
After adjusting for age, sex, education and APOE4 carrier status, the researchers found a statistically significant relationship between lower BMI and greater PiB retention, indicating higher amyloid burden. The effect was most apparent among participants with a normal BMI (the group with the lowest average BMI in the cohort). Secondary analyses showed that the association between lower BMI and higher amyloid was particularly pronounced in APOE4 carriers, and a significant interaction between BMI and APOE4 status suggested that genetic risk modifies the BMI–amyloid relationship.
One plausible explanation proposed by the authors is that low BMI late in life may be a marker for frailty—a clinical syndrome that includes unintentional weight loss, slowed movement, and loss of strength—and frailty has been linked to higher dementia risk. The team emphasizes that cross-sectional findings cannot establish causation. To better understand directionality and mechanism, HABS will follow participants over time to determine whether lower baseline BMI predicts cognitive decline or progression toward symptomatic Alzheimer’s, and whether changes in weight influence outcomes.
The study’s lead author is David C. Hsu, MD, formerly of MGH and BWH and now at Mercy Medical Group in Sacramento, California. Other co-authors include investigators from the Harvard Aging Brain Study and the Massachusetts Alzheimer’s Disease Research Center. Funding for this research came from NIH/NIA grants supporting HABS and related projects, as well as K- and P-series awards and institutional Alzheimer’s research center support.
Study design: Cross-sectional analysis of 280 cognitively normal older adults (ages 62–90) from the Harvard Aging Brain Study. Measures included BMI, medical history, APOE4 genotyping, and PiB-PET imaging for cortical amyloid.
Main findings: Lower BMI in late life was associated with higher cortical amyloid burden (greater PiB retention) after accounting for age, sex, education, and APOE4 status. The association was most evident in participants with normal BMI and in APOE4 carriers. A significant BMI×APOE4 interaction indicates genetic risk may amplify the relationship between low BMI and amyloid deposition.
Implications: These results add to evidence that weight loss or low body mass in older adults can be associated with biological markers of Alzheimer’s disease. Longitudinal follow-up is needed to determine whether lower BMI precedes cognitive decline and to explore mechanisms—such as frailty, metabolic changes, or other biological processes—that could link body composition and amyloid accumulation.
This research was supported by the Harvard Aging Brain Study (NIH/NIA grants P01 AG036694, R01 AG037497, R01 AG046396), K23 AG033634, K24 AG035007, and the Massachusetts Alzheimer’s Disease Research Center (P50 AG005134). The full report, “Lower Late-Life Body-Mass Index is Associated with Higher Cortical Amyloid Burden in Clinically Normal Elderly,” was published online in the Journal of Alzheimer’s Disease (June 18, 2016).
For clinicians, researchers and older adults, these findings underscore the importance of monitoring weight and general health in late life as potential indicators of brain health. Ongoing HABS follow-up will help clarify whether interventions to maintain or increase BMI in late life influence amyloid accumulation or clinical outcomes.