The co-occurrence of cardiometabolic diseases (CMDs) is increasingly prevalent and has been associated with an additive risk of dementia in older adults, but the extent to which this risk can be offset by a healthy lifestyle is unknown. We aimed to examine the associations of cardiometabolic multimorbidity and lifestyle with incident dementia and related brain structural changes.This prospective study extracted health and lifestyle data from 171 538 UK Biobank participants aged 60 years or older without dementia at baseline between 2006 and 2010 and followed up until July 2021, as well as brain structural data in a nested imaging subsample of 11 972 participants. Cardiometabolic multimorbidity was defined as the presence of two or more CMDs among type 2 diabetes, coronary heart disease, stroke, and hypertension. Lifestyle patterns were determined based on 7 modifiable lifestyle factors including smoking, alcohol consumption, physical activity, diet, sleep duration, sedentary behavior, and social contact.Over a median follow-up of 12.3 years, 4479 (2.6%) participants developed dementia. The presence of CMDs was dose-dependently associated with an increased risk of dementia. Compared with participants with no CMDs and a favourable lifestyle, those with ≥ 3 CMDs and an unfavourable lifestyle had a five times greater risk of developing dementia (HR 5.33, 95% CI 4.26-6.66). A significant interaction was found between CMD status and lifestyle (Pinteraction=0.001). The absolute difference in incidence rates of dementia per 1000 person years comparing favourable versus unfavourable lifestyle was - 0.65 (95% CI - 1.02 to - 0.27) among participants with no CMDs and - 5.64 (- 8.11 to - 3.17) among participants with ≥ 3 CMDs, corresponding to a HR of 0.71 (0.58-0.88) and 0.42 (0.28-0.63), respectively. In the imaging subsample, a favourable lifestyle was associated with larger total brain, grey matter, and hippocampus volumes across CMD status.Our findings suggest that adherence to a healthy lifestyle might substantially attenuate dementia risk and adverse brain structural changes associated with cardiometabolic multimorbidity.© 2023. BioMed Central Ltd., part of Springer Nature.