Different associations between body mass index and Alzheimer’s markers depending on metabolic health

Abstract Background Increasing evidence supports the association between body mass index (BMI), Alzheimer’s disease, and vascular markers. Recently, metabolically unhealthy conditions have been reported to affect the expression of these markers. We aimed to investigate the effects of BMI status on Alzheimer’s and vascular markers in relation to metabolic health status. Methods We recruited 1,736 Asians without dementia (71.6 ± 8.0 years). Participants were categorized into underweight, normal weight, or obese groups based on their BMI. Each group was further divided into metabolically healthy (MH) and unhealthy (MU) groups based on the International Diabetes Foundation definition of metabolic syndrome. The main outcome was Aβ positivity, defined as a Centiloid value of 20.0 or above and the presence of vascular markers, defined as severe white matter hyperintensities (WMH). Logistic regression analyses were performed for Aβ positivity and severe WMH with BMI status or interaction terms between BMI and metabolic health status as predictors. Mediation analyses were performed with hippocampal volume (HV) and baseline Mini-Mental State Examination (MMSE) scores as the outcomes, and linear mixed models were performed for longitudinal change in MMSE scores. Results Being underweight increased the risk of Aβ positivity (odds ratio OR = 2.37, 95% confidence interval CI 1.13–4.98), whereas obesity decreased Aβ positivity risk (OR = 0.63, 95% CI 0.50–0.80). Especially, obesity decreased the risk of Aβ positivity (OR = 0.38, 95% CI 0.26–0.56) in the MH group, but not in the MU group. Obesity increased the risk of severe WMH (OR = 1.69, 1.16–2.47). Decreased Aβ positivity mediate the relationship between obesity and higher HV and MMSE scores, particularly in the MH group. Obesity demonstrated a slower decline in MMSE (β = 1.423, p = 0.037) compared to being normal weight, especially in the MH group. Conclusions Our findings provide new evidence that metabolic health has a significant effect on the relationship between obesity and Alzheimer’s markers, which, in turn, lead to better clinical outcomes.