Prediabetes, intervening diabetes and subsequent risk of dementia: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis: The aim of this work was to evaluate whether the association of prediabetes with dementia is explained by the intervening onset of diabetes. Methods: Among participants of the Atherosclerosis Risk in Communities (ARIC) study we defined baseline prediabetes as HbA_1c 39–46 mmol/mol (5.7–6.4%) and subsequent incident diabetes as a self-reported physician diagnosis or use of diabetes medication. Incident dementia was ascertained via active surveillance and adjudicated. We quantified the association of prediabetes with dementia risk before and after accounting for the subsequent development of diabetes among ARIC participants without diabetes at baseline (1990–1992; participants aged 46–70 years). We also evaluated whether age at diabetes diagnosis modified the risk of dementia. Results: Among 11,656 participants without diabetes at baseline, 2330 (20.0%) had prediabetes. Before accounting for incident diabetes, prediabetes was significantly associated with the risk of dementia (HR 1.12 [95% CI 1.01, 1.24]). After accounting for incident diabetes, the association was attenuated and non-significant (HR 1.05 [95% CI 0.94, 1.16]). Earlier age of onset of diabetes had the strongest association with dementia: HR 2.92 (95% CI 2.06, 4.14) for onset before 60 years; HR 1.73 (95% CI 1.47, 2.04) for onset at 60–69 years; and HR 1.23 (95% CI 1.08, 1.40) for onset at 70–79 years. Conclusions/interpretation: Prediabetes is associated with dementia risk but this risk is explained by the subsequent development of diabetes. Earlier age of onset of diabetes substantially increases dementia risk. Preventing or delaying progression of prediabetes to diabetes will reduce dementia burden. Graphical Abstract: [Figure not available: see fulltext.].