Abstract
BACKGROUND: Obesity is a major global health challenge, linked to cardiometabolic and neuropsychiatric disorders through mechanisms such as inflammation and insulin resistance. However, little is known about how adiposity and its longitudinal changes interact with glycemic status to shape neuropsychiatric health and brain structural vulnerability. Clarifying these relationships is of high importance, as both obesity and dysglycemia are modifiable risk factors that may jointly accelerate psychiatric disorder and brain aging. METHODS: Using UK Biobank data (n = 423,750, with 32,551 having brain MRI), we examined associations between obesity indicators (body mass index [BMI], waist circumference [WC], body fat percentage [BFP]) and changes in obesity status with incident neuropsychiatric disorders (stroke, dementia, Parkinson's disease, depression, anxiety) and brain structural measures. Participants were stratified by glycemic status-normal glucose regulation (NGR), prediabetes (Pre-DM), and diabetes (DM)-based on American Diabetes Association criteria. Cox proportional hazards and linear regression models were used. RESULTS: Higher BMI, WC, and BFP were associated with increased risks of depression and anxiety across all glycemic groups, particularly in NGR. Abdominal obesity was linked to Parkinson's disease risk in NGR. Conversely, BMI showed an inverse association with dementia in NGR, possibly due to reverse causality. Persistent obesity and weight gain were associated with higher depression and anxiety risks in NGR. In diabetes, higher BFP was strongly linked to reduced grey matter, thalamus, and hippocampus volumes and increased WMHs. This association with BFP represented the most robust imaging signal, highlighting the pronounced vulnerability of brain structure to excess adiposity in diabetes. Similar but weaker patterns were observed in prediabetes and NGR. CONCLUSION: Obesity, particularly persistent or increasing adiposity, adversely affects neuropsychiatric health and brain structure, and these effects are significantly modified by glycemic status. Our findings underscore the importance of considering glucose metabolism when assessing obesity-related brain risks, and suggest that early weight management and metabolic control may have broad benefits for preventing neuropsychiatric disorders and mitigating brain aging.