Dementia risk in relation to obesity and metabolic health phenotypes in midlife and late-life

Background Midlife obesity is a well-established risk factor for dementia, whereas late-life obesity has been associated with no increased risk, or even a reduced risk in some studies. However, the joint associations of obesity (body mass index ≥ 30 kg/m ² ) and metabolic health phenotypes (defined by the presence of hyperglycemia, hypertension and dyslipidemia) with dementia risk are less explored, particularly with regard to age- and sex-related differences. Therefore, we investigated how obesity and metabolic health phenotypes jointly associate with dementia risk and whether this risk differs between midlife (≤ 65 years) and late-life (> 65 years), and sex. Material and Methods We analysed data from 11,482 participants, aged 51 to 100 years, from the US Health and Retirement Study (HRS), and 13,068 participants, aged 45 to 90 years, from the Swedish Twin Registry (STR). Cox regression models were used to estimate dementia risk in relation to metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), and metabolically unhealthy no obesity (MUNO), relative to metabolically healthy no obesity (reference). Models were adjusted for age, sex, smoking status, and education level. Analyses were stratified by midlife and late-life and conducted in the entire sample and separately by sex. Results Metabolically unhealthy status in midlife and late-life indicated increased dementia risk regardless of obesity status, reaching statistical significance for midlife MUNO in females in HRS (Hazard ratio (HR): 1.62, 95% confidence intervals (CI): 1.05–2.49) and in late-life MUNO for the full sample in STR (HR: 1.13, CI: 1.02–1.25) and males in the STR (HR: 1.22, CI: 1.04–1.42). The associations between MUO and dementia risk were not statistically significant, but trends suggested midlife MUO was associated with higher dementia risk. The associations between mid and late-life MHO with dementia risk were also not statistically significant, although the associations showed trends towards lower dementia risk. Conclusions Being metabolically unhealthy, especially in midlife, may be associated with increased dementia risk, regardless of obesity status. Mid- and late-life MHO showed no increased risk and suggested potential inverse associations. These findings underscore the importance of evaluating dementia risk in the context of obesity, metabolic health, age and sex simultaneously.