Introduction: Diabetes is associated with both dementia and death. Ignoring the competing risk of mortality may result in overestimation of the lifetime of dementia. Hypothesis: The lifetime cumulative incidence of dementia associated with diabetes will be much lower when taking into account the competing risk of mortality, particularly at the oldest ages. Methods: We conducted a prospective cohort analysis of data from the Atherosclerosis Risk in Communities (ARIC) Study (midlife baseline at visit 2, 1990-1992). Diabetes was defined as a self-reported physician diagnosis, diabetes medication use, or HbA1C of 6.5% or greater. Incident dementia was ascertained via active surveillance involving interviews and adjudication. We conducted survival analysis using age as the time scale with age 50 as the origin and December 31st, 2019 as the administrative censoring date. Dementia risk was analyzed with death treated as a censoring event or as a competing risk. Results: Among 13,381 participants, 1798 (13.4%) had diabetes at baseline (mean age: 56.8 years). Using a standard Cox model, diabetes was associated with an increased hazard of dementia (HR 1.36; 95% CI 1.21, 1.52) and death (HR 1.87; 95% CI 1.76, 1.99). Censoring mortality (ignoring competing risk), diabetes was associated with a higher cumulative incidence of dementia at all ages ( Figure A ). Competing risk models showed a lower risk of dementia than models censoring death. Furthermore, diabetes was associated with a higher risk of dementia only before age 85 but a lower cumulative risk after age 85 due to the large excess risk of mortality ( Figures B and C ). Conclusion Standard methods dramatically overestimate the lifetime risk of dementia in persons with and without diabetes. Competing risk models are critical for accurate absolute risk estimates, particularly in the oldest ages. Interventions which increase life expectancy in patients with diabetes may increase the cumulative risk of dementia in old age.
Objective: To characterize the direct and indirect association of prediabetes with dementia risk and to examine the age at diabetes onset and subsequent risk of dementia. Methods: At baseline (1990-1992), prediabetes was defined based on HbA1C 5.7-6.4% among people without a history of diagnosed diabetes or medication use for diabetes; diabetes was defined based on self-reported physician diagnosis or diabetes medication use or HbA1C level of 6.5% or greater. Incident diabetes with the same definition during the follow-up was included as a time-varying variable. Incident dementia was ascertained using surveillance, interviews and adjudication. Survival analysis used age as the time scale using an origin at age 50 and left and right censoring. Adjustment models included sex, race, education, APOE, BMI, smoking status, alcohol use, physical activity, total cholesterol, HDL cholesterol and hypertension. Results: Among the 13,388 participants, 2314 (17.3%) had prediabetes and 1798 (13.4%) had diabetes at baseline. Before adjusting for incident diabetes, the adjusted hazard ratios of dementia were 2.35 (95% CI: 1.99, 2.76) and 1.13 (95% CI: 1.02, 1.25) for diabetes and prediabetes compared to no diabetes in the fully adjusted model. After adding incident diabetes, the excess risk of dementia for prediabetes decreased by ~50% and the association was not significant. The relative hazards of dementia were 3.16 (95% CI: 2.15, 4.66), 1.64 (95% CI: 1.36, 1.97), 1.29 (95% CI: 1.14, 1.47) and 1.06 (95% CI: 0.89, 1.28) for diabetes with age onset at < 60, 60-69, 70-79 and 80-93, respectively (Table). Conclusion: Midlife diabetes and prediabetes are associated with excess hazard of dementia and death. Earlier age of onset of diabetes shows a strong dose response with higher dementia hazard. Much of the risk of dementia in pre-diabetes is explained by intervening incidence of clinical diabetes. Dementia prevention efforts would benefit from preventing or delaying the progression of prediabetes to diabetes.
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