BMI Decline Patterns and Relation to Dementia Risk Across Four Decades of Follow-Up in the Framingham Study

Background: Obesity has been associated with increased risk of dementia with several studies reporting a reverse causality, where weight loss precedes the onset of dementia. We leveraged four decades of longitudinal body mass index (BMI) data from the Framingham Heart Study (FHS) to determine the directionality of the relationship between BMI decline and dementia. Methods: 2045 non-demented Framingham Offspring participants, aged 30-50 years at their second exam were included in this study. We determined the effect of BMI at baseline, BMI changes, and BMI decline patterns from mid- to late life over a 39-year follow-up. Group-based trajectory models were used to create BMI trajectories. Different patterns of BMI decline were compared to non-decliners to investigate the associations between BMI trajectories and dementia. Findings: Decreasing BMI trends was associated with a higher risk of developing dementia in late life. Decliners with first early mid-life increasing and then later midlife decreasing patterns of BMI were at a greater increased risk of dementia compared to non-decliners (HR 4.51, 95% CI 1.59-12.76). Accounting for competing risk of death attenuated estimates but did not change inferences. Interpretation: While patterns of decline in BMI were associated with dementia, a subgroup with a pattern of initial increasing BMI followed by decreasing BMI at midlife appeared to be central to this BMI-dementia association. These results support the concept of reverse causality and reinforce the concept of dementia as a life-course disease, where monitoring factors such as weight changes may mediate risk for dementia across an individual’s lifetime. Funding: The study was supported by Healthy Longevity Global Competition (2021-JKCS-023), the Framingham Heart Study’s National Heart, Lung, and Blood Institute contract (N01-HC-25195), the National Institute on Aging (AG016495, AG008122, AG033040, AG062109, AG049810, AG054156, AG062109, AG068753), National Institute of Neurological Disorders and Stroke (R01-NS017950) and VMF-14-318524 from the Alzheimer’s Association and Pfizer. Declaration of Interest: None to declare. Ethical Approval: All study participants provided written informed consent. The study protocols and consent forms were approved by the Boston University Medical Campus and Boston Medical Center Institutional Review Board.