Age at type 2 diabetes onset and risk of dementia: The modifying role of genetic susceptibility and mitochondrial function

• Incident T2D was associated with higher risks of all-cause dementia, AD, and VaD. • Dementia risk heterogeneity was observed across T2D age-at-diagnosis groups. • Glucose-lowering treatment initiation was associated with lower dementia risk. • PRS and mtDNA-CN modified associations between incident T2D and dementia. • Low PRS plus low mtDNA-CN showed the strongest AD-risk signal at ages 55–64 years. To assess dementia risk after incident type 2 diabetes (T2D) by age at diagnosis and evaluate modification by treatment, genetic susceptibility, and mitochondrial function. Prospective 1:1 age- and sex-matched cohort study using inverse-probability-weighted Cox models. Kunshan Aging Research with E-health (KARE) cohort in China (2018–2024). 42,514 adults without diabetes or dementia at baseline, including 21,257 incident T2D cases and 21,257 non-diabetic controls. Outcomes were all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) from linked medical records and annual examinations. T2D onset age was grouped as 45–54 years, 55–64 years, and persons 65 years and older. In genotyped participants ( n = 14,455), a T2D polygenic risk score (PRS) and blood mitochondrial DNA copy number (mtDNA-CN) were examined. Over a median 3.67 years, incident T2D was associated with higher risks of all-cause dementia (adjusted hazard ratio [AHR] 1.95, 95% CI 1.71–2.21), AD (2.21, 1.88–2.59), and VaD (1.57, 1.20–2.07). Glucose-lowering treatment was associated with lower dementia risk versus no treatment. Among patients aged 55–64 years, the low-PRS/low-mtDNA-CN subgroup had the highest AD risk (AHR 2.41, 95% CI 1.12–5.19). Age at T2D onset was associated with variation in dementia risk. Earlier diagnosis and treatment were associated with lower observed cognitive risk, while genetic susceptibility and mitochondrial function may inform individualised risk stratification.