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

OBJECTIVES

To assess dementia risk after incident type 2 diabetes (T2D) by age at diagnosis and evaluate modification by treatment, genetic susceptibility, and mitochondrial function.

DESIGN

Prospective 1:1 age- and sex-matched cohort study using inverse-probability-weighted Cox models.

SETTING

Kunshan Aging Research with E-health (KARE) cohort in China (2018-2024).

PARTICIPANTS

42,514 adults without diabetes or dementia at baseline, including 21,257 incident T2D cases and 21,257 non-diabetic controls.

MEASUREMENTS: 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.

RESULTS

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).

CONCLUSION

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.