Background: Young-onset dementia (YOD, onset <65 years) is an emerging public health challenge affecting over 200,000 Americans, yet risk factor other than genetics remain poorly defined. Neighborhood socioeconomic deprivation has been linked to late-life dementia, but its relationship with YOD is unclear. We investigated whether higher neighborhood deprivation increases YOD risk in a large, diverse U.S. cohort.

Methods: We conducted a retrospective cohort study using All of Us Research Program data. Participants (N=180,549) were aged <60 years, dementia-free at enrollment (2017–2022), and were followed for incident YOD through mid-2022 (mean follow-up 33 months). Neighborhood deprivation was assessed via the Neighborhood Deprivation Index (NDI) at baseline, a census block-group composite of community poverty, education, income, employment, and housing conditions. NDI was categorized into quintiles (Q1=least deprived, Q5=most deprived). Incident YOD was defined as any dementia diagnosis (ICD-9/10) occurring before age 65. We used Cox proportional hazards models to estimate hazard ratios (HRs) for all-cause YOD and subtypes (young-onset Alzheimer’s disease [AD] or vascular dementia) across NDI levels. Restricted cubic spline analyses and interaction terms tested dose–response relationships and effect modification by sex, race/ethnicity, APOE-ε4 genotype, age, country of birth, and family history of dementia. 

Results: 180,549 participants (Figure 1) were included (mean age 53.8 years; 52% female). During follow-up, 878 developed YOD, including 466 Alzheimer’s disease and 244 vascular dementia. In fully adjusted analyses, the most deprived quintile had a 44% higher hazard of all-cause YOD (95%CI 1.01–2.05) and nearly double the hazard of young-onset AD (HR 1.94, 95%CI 1.11–3.38) versus Q1. Each 1% increase in NDI corresponded to ~2.6% higher all-cause YOD risk (HR 1.026) and ~3.9% higher young-onset AD risk (HR 1.039; Figure 2, Table 1). Results were consistent across subgroups defined by age, APOE-ε4 status, and family history. However, significant effect modification by sex and race/ethnicity was observed: the association was more pronounced in women and in non-Hispanic Black participants, while it did not vary by APOE status.

Conclusions: Neighborhood deprivation is an important and potentially modifiable risk factor for YOD. Public health efforts to improve neighborhood conditions may help reduce the burden of YOD.