Abstract
BackgroundResearch has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI.Methods and FindingsThe first cohort, which included dementia-free adults aged ≥75 y (n = 970) at baseline, was followed for 9 y to detect incident dementia (n = 358) and AD (n = 271) cases. The second cohort (for replication), which included 2,060 dementia-free participants aged ≥60 y at baseline, was followed for 6 y to identify incident dementia (n = 166) and AD (n = 121) cases. A subsample (n = 338) of dementia-free participants from the second cohort underwent MRI. HHEX_23 and IDE_9 were genotyped, and diabetes (here including type 2 diabetes and prediabetes) was assessed. In the first cohort, diabetes led to an adjusted hazard ratio (HR) of 1.73 (95% CI 1.19–2.32) and 1.66 (95% CI 1.06–2.40) for dementia and AD, respectively, among all participants. Compared to people carrying the GG genotype without diabetes, AA genotype carriers with diabetes had an adjusted HR of 5.54 (95% CI 2.40–7.18) and 4.81 (95% CI 1.88–8.50) for dementia and AD, respectively. There was a significant interaction between HHEX_23-AA and diabetes on dementia (HR 4.79, 95% CI 1.63–8.90, p = 0.013) and AD (HR 3.55, 95% CI 1.45–9.91, p = 0.025) compared to the GG genotype without diabetes. In the second cohort, the HRs were 1.68 (95% CI 1.04–2.99) and 1.64 (1.02–2.33) for the diabetes–AD and dementia–AD associations, respectively, and 4.06 (95% CI 1.06–7.58, p = 0.039) and 3.29 (95% CI 1.02–8.33, p = 0.044) for the interactions, respectively. MRI data showed that HHEX_23-AA carriers with diabetes had significant structural brain changes compared to HHEX_23-GG carriers without diabetes. No joint effects of IDE_9 and diabetes on dementia were shown. As a limitation, the sample sizes were small for certain subgroups.ConclusionsA variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people.
Highlights
An increased risk of dementia and Alzheimer disease (AD) in people with type 2 diabetes has been found in numerous prospective population-based studies, including several meta-analyses using pooled data [1,2,3]
In crude and multi-adjusted logistic regression analysis, compared to the HHEX_23-GG genotype, the HHEX_23-AG genotype and the AA genotype were significantly associated with diabetes in the two cohorts (Table 2)
In fully adjusted Cox regression analysis, diabetes was associated with a more than 60% increased risk of dementia (HR 1.73, 95% CI 1.19–2.32) and AD (HR 1.66, 95% CI 1.06–2.40) after controlling for age, sex, education, baseline Mini-Mental State Examination (MMSE) score, body mass index (BMI), heart disease, stroke, systolic blood pressure (SBP), diastolic blood pressure (DBP), APOE ε4, and survival status
Summary
An increased risk of dementia and Alzheimer disease (AD) in people with type 2 diabetes has been found in numerous prospective population-based studies, including several meta-analyses using pooled data [1,2,3]. Even prediabetes has been found to be predictive of an increased risk of dementia and AD [4,5] Mechanisms for such an association remain unclear. Research has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI. Affected individuals may lose control of various physical functions and many become totally dependent on specialist nurses and other professional carers for their day-to-day needs
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