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.

Abstract

To investigate the independent and combined associations of type 2 diabetes (T2D) and APOE genotype on dementia risk. 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. 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. 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.