Late-life body mass index and amyloid interaction on cognitive decline in unimpaired older adults.

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.