Risk factors for early-onset and late-onset dementia: a prospective cohort study

BACKGROUND: Early-onset dementia (onset before age 65 years) is an important health concern, but much of our understanding of its risk factors is inferred from studies of late-onset dementia (onset after age 65 years). We investigated associations between several demographic, clinical, and lifestyle factors with early-onset dementia and compared those estimates against their associations with late-onset dementia. METHODS: Data from five community-based longitudinal cohort studies from the UK and USA were pooled and rigorously harmonised: UK Biobank, Atherosclerosis Risk in Communities Study, Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, and Whitehall II Study. Dementia was ascertained via hospitalisation and death records with or without clinical assessments according to each cohort's protocol. Risk factors included sex, self-reported race or ethnicity (Hispanic, White, Black, Asian, and Other), low education, hypertension, diabetes, obesity, hypercholesterolaemia, depression, alcohol overconsumption, smoking, and physical inactivity. Cox regression models, with age as the timescale and time-varying coefficients, were fitted to estimate hazard ratios (HRs) for early-onset dementia and late-onset dementia and to test whether the HRs differed by age of onset. FINDINGS: In 544 442 participants, there were 807 incident early-onset dementia cases and 14 253 incident late-onset dementia cases over a median follow-up of 13·7 years (IQR 12·9-14·4). Female participants had a lower hazard of early-onset dementia compared with males (HR 0·70 95% CI 0·61-0·80). Black versus White race (1·61 1·23-2·11), grade school education or less (1·99 1·67-2·38), diabetes (2·45 1·99-3·03), depression (2·73 2·34-3·20), smoking (1·86 1·56-2·22), obesity (1·24 1·04-1·48), physical inactivity (1·33 1·11-1·59), and alcohol overconsumption (1·22 1·01-1·47) were independently associated with higher hazards of early-onset dementia. Hypertension stage 1 (HR 1·19 95% CI 0·97-1·47), hypertension stage 2 (1·16 0·94-1·43), and hypercholesterolaemia (1·11 0·92-1·34) had positive effect estimates but were not statistically significant. All risk factors had stronger associations with early-onset dementia than with late-onset dementia except race, physical inactivity, and alcohol overconsumption. INTERPRETATION: Our findings demonstrate the importance of modifiable risk factors in the development of early-onset dementia and guide future research for identifying high-priority targets for primary prevention. FUNDING: US National Institutes of Health, the National Institute for Neurologic Disorders and Stroke, and the National Institute of Aging.