Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults - 08/04/26
, Rema Raman c, Jasmeer Chhatwal a, b, Jeremy J. Pruzin d, Zahra Shirzadi a, b, Neelum Aggarwal e, Adam M. Brickman f, Petrice M. Cogswell g, Jonathan Graff-Radford h, Jay J. Pillai g, i, Prashanthi Vemuri g, Michael S. Rafii c, Roy Yaari j, Paul Aisen c, Reisa Sperling a, b, 2, ⁎ The A4 and LEARN Study Teams
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Highlights |
• | We examined the joint associations of BMI and amyloid with cognition in a cohort enriched for preclinical Alzheimer’s disease (AD). |
• | Late-life obesity and amyloid pathology were independently associated with poorer baseline cognition. |
• | Longitudinally, the BMI–cognition relationship was modified by amyloid burden. |
• | Lower or normal BMI was associated with faster cognitive decline only when amyloid burden was high, independent of weight loss. |
• | Future AD prevention trials with obesity interventions may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation. |
Abstract |
Background |
The late-life “obesity paradox” of reduced Alzheimer’s disease (AD) risk is postulated to be driven by underlying preclinical/prodromal pathology. However, few studies have directly examined the joint associations of BMI and amyloid pathology with cognitive decline, especially in individuals with preclinical AD targeted in prevention trials.
Objective |
To determine whether late-life BMI and amyloid pathology have independent or interactive associations with cognition in clinically unimpaired older adults.
Design |
Secondary analyses of A4 randomized clinical trial and the companion observational LEARN Study (median follow-up 4.7 years).
Setting |
Multicenter across 67 sites in US, Canada, Australia, and Japan.
Participants |
We included 1663 participants (Placebo n = 582, Solanezumab n = 563, LEARN n = 518) who were baseline cognitively unimpaired and medically stable, mean age 71.5 ± 4.7 years, 60% women.
Measurements |
BMI and global amyloid burden [Florbetapir PET] were measured at baseline. Cognition was measured longitudinally using Preclinical Alzheimer Cognitive Composite.
Results |
Higher BMI and amyloid burden were independently associated with worse baseline cognition. Longitudinally, a BMI*Amyloid*Time interaction emerged: lower/normal BMI was associated with more favorable cognitive trajectory at low amyloid levels, but with faster cognitive decline when amyloid was substantially elevated.
Conclusions |
Our cross-sectional findings support a negative association between obesity and cognitive aging up to late-life. Longitudinally, we observed an “obesity paradox”, where higher/obese BMI was associated with more favorable cognitive trajectories in the presence of advanced amyloid pathology. Together, our findings suggest that future trials targeting obesity to slow late-life cognitive decline may benefit from preferentially enrolling younger individuals or those without substantial amyloid accumulation.
Le texte complet de cet article est disponible en PDF.Keywords : Preclinical Alzheimer's disease, BMI, Obesity paradox, Amyloid, Cognitive decline, Aging
Plan
Vol 13 - N° 5
Article 100543- mai 2026 Retour au numéro
Article précédent
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