Incidence and synergistic Association of Type 2 diabetes and apolipoprotein E epsilon 4 with dementia risk in the Kunshan aging research with E-health cohort study

OBJECTIVE: To investigate the independent and combined associations of type 2 diabetes (T2D) and APOE genotype on dementia risk. METHODS: We analyzed 104,911 participants aged ≥50 years from the Kunshan Aging Research with E-Health cohort (2018-2024). Incident dementia was identified using electronic medical records. Cox proportional hazards models and additive interaction analyses assessed associations and interactions. RESULTS: Over a median follow-up of 6.19 years, 8115 participants developed dementia. T2D was associated with higher risks of all-cause dementia (HR:2.06), Alzheimer's disease (HR:2.16), and vascular dementia (HR:1.62). APOE ε4 carriers had higher Alzheimer's risk (HR:1.35), while ε2 carriers had lower risk (HR:0.87). The combination of T2D and ε4 was associated with the highest Alzheimer's risk (HR:2.87) with a significant positive additive interaction. In men, T2D interacted with ε2 on a multiplicative scale, whereas in women, a positive additive interaction was observed between T2D and ε2 for Alzheimer's disease. CONCLUSIONS: T2D was associated with higher dementia risk. APOE ε4 was associated with higher and ε2 with lower Alzheimer's risk. A positive additive T2D-ε4 interaction and sex-specific ε2 associations underscore integrating diabetes management with genetic profiling to optimize dementia risk reduction strategies.