The obesity paradox in cognitive decline: Impact of BMI dynamics and APOE genotypes across various cognitive status

To explore the relationship between body mass index (BMI) and its changes in relation to cognitive decline across different cognitive status, while also examining the role of the APOE genotype in these associations.

A total of 23 255 individuals from the National Alzheimer's Coordinating Center (NACC) were analysed using multivariable logistic and Cox regression to assess BMI and its variability in relation to cognitive decline. Subgroup analyses were conducted to explore how APOE genotype interacts with BMI and cognitive decline.

Compared to individuals with normal cognition and normal BMI, being underweight was associated with a higher risk of developing MCI (HR 3.065, 95% CI: [1.156-8.126]) and dementia (HR 4.057, 95% CI: [1.433-11.483]). Over the 4.07-year follow-up, 9171 individuals experienced cognitive decline. Longitudinal analysis revealed that being overweight or obese was linked to a lower risk of cognitive decline across different cognitive status, including impaired not MCI, MCI and dementia, but had no effect on those with normal cognition. Additionally, compared to stable BMI, the hazard ratios (95% CI) for developing dementia were 2.336 (2.128-2.565) and 2.338 (2.119-2.581) for annual BMI gain or loss greater than 5%. However, different APOE genotypes may influence the effect of BMI and BMI variability on cognitive decline.

This research supports the 'obesity paradox' and highlights the critical role of APOE in modulating BMI's influence on cognitive health.