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 2.40–7.18) 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.
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.
In a longitudinal study, Weili Xu and colleagues explore whether variants in two insulin pathway genes modify the association of type 2 diabetes with dementia and AD.
Worldwide, about 44 million people have dementia, a group of degenerative, incurable brain disorders that mainly affect older people. Dementia is characterized by an irreversible decline in memory, communication, and other “cognitive” functions. The most common forms of dementia are Alzheimer disease, which is caused by the development of small clumps of proteins (β-amyloid plaques) around brain cells, and vascular dementia, which is caused by reduced blood flow to parts of the brain. Early symptoms of dementia include increasing forgetfulness and losing track of time. As the condition progresses, affected individuals gradually lose the ability to look after themselves and to communicate, and they may become anxious or aggressive. Eventually, 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.
Why Was This Study Done?
Epidemiological studies (investigations that examine patterns of disease in populations) suggest that, among older individuals, having type 2 diabetes (a condition in which resistance to the hormone insulin leads to high blood sugar levels) is associated with a 50% increased risk of developing dementia. Even prediabetes (a blood sugar level that is high but not high enough to meet the criteria for diabetes) is associated with an increased risk of dementia. Prediabetes and diabetes increase the risk of vascular disease, but it is thought that polymorphisms (naturally occurring genetic variations) in the IDE/HHEX region of the human genome may be involved in the association between diabetes and dementia/Alzheimer disease. IDE encodes insulin-degrading enzyme, which clears insulin from cells but also degrades β-amyloid; HHEX encodes a transcription factor that controls IDE expression. In this population-based longitudinal study, the researchers explore whether two single nucleotide polymorphisms in this region—IDE_9 and HHEX_23—impact the association between diabetes and dementia. Population-based longitudinal studies measure the baseline characteristics of individuals in the general population and determine which individuals subsequently develop specific conditions.
What Did the Researchers Do and Find?
For their study, the researchers examined data collected from two cohorts (groups) of dementia-free elderly adults living in Stockholm, Sweden. Blood samples taken from 3,030 participants at baseline were used to determine which individuals had diabetes (type 2 diabetes or prediabetes) and to investigate which HHEX_23 and IDE_9 variants each individual carried (genotyping). The researchers also examined the brain structure of a subsample of the second cohort using magnetic resonance imaging (MRI). All the participants were followed for several years to see which individuals developed dementia/Alzheimer disease. In both cohorts, having diabetes was associated with a 60% increased risk of dementia/Alzheimer disease after adjusting for other characteristics that affect the development of these conditions. Pooled data from both cohorts indicated that, compared to people without diabetes carrying HHEX_23-GG (the human genome contains two copies [alleles] of each gene, and an individual carrying HHEX_23-GG has the nucleotide guanine at a particular position in both HHEX_23 copies), people with diabetes carrying HHEX_23-AA (adenine at that position in both HHEX_23 copies) had a 5-fold higher risk of developing dementia/Alzheimer disease. Other analyses indicated that the HHEX_23-AA genotype interacted with diabetes to substantially increase the risk of dementia/Alzheimer disease. Finally, MRI showed that, at baseline, HHEX_23-AA carriers with diabetes had structural brain changes compared to HHEX_23-GG carriers without diabetes, even though they were all free of dementia at the time.
What Do These Findings Mean?
These and other findings indicate that polymorphisms in HHEX_23, but not IDE_9, are involved in the association between diabetes, dementia, and structural brain changes. Thus, a genetic variant in HHEX_23 may play an important role in the development of Alzheimer disease and other forms of dementia among people with diabetes or prediabetes. These findings may not apply to younger or rural populations, and their accuracy may be affected by the use of a single blood sugar level reading to diagnose diabetes and prediabetes. Moreover, because some of the genotype/diabetes subgroups contained very few people, these findings need to be confirmed in additional studies. Further studies are also needed to understand the role of HHEX_23 in the association between diabetes and dementia. Importantly, however, these findings highlight the need to control diabetes to prevent the development of Alzheimer disease and other forms of dementia, particularly among HHEX_23-AA carriers.
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001828.
The UK National Health Service Choices website provides information (including personal stories and links to additional resources) about dementia, vascular dementia, Alzheimer disease, and diabetes
The UK not-for-profit organization Alzheimer’s Society provides information for patients and carers about dementia, including personal experiences of dementia
The US not-for-profit organization Alzheimer’s Association also provides information for patients and carers about dementia, personal stories about dementia, and information about the association between diabetes and dementia
Alzheimer’s Disease International is the federation of Alzheimer disease associations around the world; it provides links to individual Alzheimer disease associations, information about dementia, and links to World Alzheimer Reports
MedlinePlus provides links to additional resources about dementia, Alzheimer disease, vascular dementia, and diabetes (in English and Spanish)
More information about the Kungsholmen Project and the Swedish National Study on Aging and Care–Kungsholmen, the projects that enrolled the cohorts used by the researchers for this study, is available