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HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study
Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden.
Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
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Number of Authors: 9
2015 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, no 7Article in journal (Refereed) Published
Abstract [en]

Background 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. Methods and Findings The 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 2.407.18) 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. Conclusions A 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.

Place, publisher, year, edition, pages
2015. Vol. 12, no 7
National Category
Gerontology, specializing in Medical and Health Sciences Geriatrics
URN: urn:nbn:se:su:diva-120472DOI: 10.1371/journal.pmed.1001853ISI: 000359150800004OAI: diva2:853663
Available from: 2015-09-14 Created: 2015-09-10 Last updated: 2015-09-14Bibliographically approved

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Gerontology, specializing in Medical and Health SciencesGeriatrics

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