Key Points

Question  Are there modifiable risk factors associated with young-onset dementia (YOD)?

Findings  In this cohort study including more than 356 052 participants in the UK Biobank, there were multiple modifiable and nonmodifiable risk factors for YOD. Alcohol use, higher formal education, and lower physical frailty (higher handgrip strength) were associated with lower risk of incidence of YOD, whereas increased risk of YOD was associated with low socioeconomic status, apolipoprotein E status, alcohol use disorder, social isolation, vitamin D deficiency, high C-reactive protein levels, hearing impairment, orthostatic hypotension, stroke, diabetes, heart disease, and depression.

Meaning  In this study, a wide range of risk factors were associated with YOD, and targeted interventions may prove effective for dementia prevention in middle-aged adults.

Abstract

Importance  There is limited information on modifiable risk factors for young-onset dementia (YOD).

Objective  To examine factors that are associated with the incidence of YOD.

Design, Setting, and Participants  This prospective cohort study used data from the UK Biobank, with baseline assessment between 2006 and 2010 and follow-up until March 31, 2021, for England and Scotland, and February 28, 2018, for Wales. Participants younger than 65 years and without a dementia diagnosis at baseline assessment were included in this study. Participants who were 65 years and older and those with dementia at baseline were excluded. Data were analyzed from May 2022 to April 2023.

Exposures  A total of 39 potential risk factors were identified from systematic reviews of late-onset dementia and YOD risk factors and grouped into domains of sociodemographic factors (education, socioeconomic status, and sex), genetic factors (apolipoprotein E), lifestyle factors (physical activity, alcohol use, alcohol use disorder, smoking, diet, cognitive activity, social isolation, and marriage), environmental factors (nitrogen oxide, particulate matter, pesticide, and diesel), blood marker factors (vitamin D, C-reactive protein, estimated glomerular filtration rate function, and albumin), cardiometabolic factors (stroke, hypertension, diabetes, hypoglycemia, heart disease, atrial fibrillation, and aspirin use), psychiatric factors (depression, anxiety, benzodiazepine use, delirium, and sleep problems), and other factors (traumatic brain injury, rheumatoid arthritis, thyroid dysfunction, hearing impairment, and handgrip strength).

Main Outcome and Measures  Multivariable Cox proportional hazards regression was used to study the association between the risk factors and incidence of YOD. Factors were tested stepwise first within domains and then across domains.

Results  Of 356 052 included participants, 197 036 (55.3%) were women, and the mean (SD) age at baseline was 54.6 (7.0) years. During 2 891 409 person-years of follow-up, 485 incident YOD cases (251 of 485 men [51.8%]) were observed, yielding an incidence rate of 16.8 per 100 000 person-years (95% CI, 15.4-18.3). In the final model, 15 factors were significantly associated with a higher YOD risk, namely lower formal education, lower socioeconomic status, carrying 2 apolipoprotein ε4 allele, no alcohol use, alcohol use disorder, social isolation, vitamin D deficiency, high C-reactive protein levels, lower handgrip strength, hearing impairment, orthostatic hypotension, stroke, diabetes, heart disease, and depression.

Conclusions and Relevance  In this study, several factors, mostly modifiable, were associated with a higher risk of YOD. These modifiable risk factors should be incorporated in future dementia prevention initiatives and raise new therapeutic possibilities for YOD.