Increased Risk of Type 2 Diabetes in Alzheimer Disease

Juliette Janson; Thomas Laedtke; Joseph E. Parisi; Peter O'Brien; Ronald C. Petersen; Peter C. Butler


Diabetes. 2004;53(2) 

In This Article


We report that the prevalence of both type 2 diabetes and IFG are increased in a well-characterized community cohort of patients with Alzheimer disease from southeast Minnesota. In the related pathology studies, we also report an increased frequency of islet amyloid in patients with Alzheimer disease. However, brain amyloid was not increased in patients with type 2 diabetes versus non-type 2 diabetes, but the density of diffuse and neuritic plaques, when present, was associated with the duration of diabetes.

The studies were initially undertaken to test the hypothesis that there may be a shared predisposition for development of islet amyloid and brain amyloid in patients with Alzheimer disease and type 2 diabetes, respectively. This postulate arose from the close resemblance in pathology in the brain in Alzheimer disease and islets in type 2 diabetes. In both diseases, a locally expressed protein (AβP in Alzheimer disease and IAPP in type 2 diabetes) is deposited in amyloid deposits with a gradual decline in the number of cells of the respective proteins. Amyloid deposits of both AβP and IAPP (or more likely their oligomeric precursors) are cytotoxic[22,23,35,36,37,38,39,40] by a mechanism that may relate to membrane disruption.[25,26,27] However, as yet, there is still no clear explanation for why these amyloidogenic proteins form amyloid fibrils in those who develop type 2 diabetes and Alzheimer disease. Because both of these proteins spontaneously form amyloid fibrils in vitro in the aqueous environment present in the cell, mechanisms must exist in health to prevent this aggregation, which presumably include the chaperone protein pathway.[30] All newly synthesized proteins are bound by a chaperone protein that has the function of preventing insoluble proteins (e.g., IAPP and AβP) from aggregating in cells and trafficking the protein to its appropriate subcellular location. Chaperon proteins have been described as promiscuous because each chaperone protein binds and traffics numerous different proteins with structurally similar properties.[30] As individual chaperone proteins traffic structurally similar peptides, it is possible that IAPP and AβP share one or more chaperone proteins. In Fig. 4, the amino acid sequence and structural properties of each amino acid of IAPP1-37 and AβP1-42 are shown. They have been aligned to reveal the major overlap (~90%) in structural properties of IAPP20-28 and AβP25-33, areas that are hydrophobic and therefore likely to be a target for binding by chaperone proteins. Furthermore, this region of IAPP is well-established as the amyloidogenic sequence[36] and AβP25-35 is neurotoxic.[41] Recently it has been suggested that the toxic intermediate form of IAPP and AβP oligomers are recognized by the same antibody, suggesting a strong structural relationship.[42]

The structural overlap between IAPP and AβP. There is a major overlap (~90%) in the structural properties of IAPP20-28 and AβP25-33 when the amino acids are classified as acidic (A), basic (B), nonpolar (NP), and polar uncharged (Pu). Gray boxed and hatched areas are identical amino acids; gray boxed areas are amino acids with similar structural properties.

If the chaperone protein pathway for trafficking AβP or IAPP is shared, then any decreased capacity for trafficking of either might also be shared. Under these circumstances, aggregation of either or both proteins might occur, resulting in the development of the relevant phenotype for Alzheimer disease and/or type 2 diabetes. In addition, type 2 diabetes and Alzheimer disease increase in prevalence with aging, and cell chaperone protein capacity declines with aging,[43] which would be expected to reveal any partial deficiency in chaperone capacity with aging. Therefore, one potential explanation for the reported shared risk for Alzheimer disease and type 2 diabetes and similar pathology is that IAPP and AβP share one or more chaperone proteins and that a functional defect in this shared pathway (decreased chaperone protein binding, decreased chaperone protein availability) results in a shared vulnerability for AβP to aggregate in β-pleated sheets in cortical cells and IAPP to aggregate in β-cells.

An alternative hypothesis to account for the reported overlap between islet amyloid and brain amyloid is that subtle hyperglycemia causes Alzheimer disease. This possibility has been reviewed by Finch and Cohen.[44] Finch and Cohen proposed that the progressive increase in plasma glucose concentration that occurs with aging in the general population may be important in the pathogenesis of Alzheimer disease. They proposed that this may be mediated by induction of oxidative stress or by glycosylation of key regulatory proteins.[45,46] The current study was at least partly supportive of this interesting hypothesis. When present, the density of diffuse and neuritic plaques in brain increased with the duration of diabetes but not with age. Prolonged exposure to hyperglycemia thus might trigger brain plaque formation in those at risk. However, against this hypothesis, there was not an overall increase in the pathological features of Alzheimer disease in cases of type 2 diabetes compared with control subjects, consistent with a previous pathological report.[47]

The high risk of underlying vascular disease in diabetes has been reported to increase rates of vascular dementia in diabetes.[48,49] Furthermore, hypertension and hyperlipidemia, both strongly associated with diabetes,[50] both are risk factors for vascular dementia.[51,52,53,54] Another potential mechanism for decreased cognitive function in long-standing diabetes is recurrent hypoglycemia.[55,56,57] However, in the present studies, we included only cases with type 2 diabetes in which recurrent hypoglycemia is rare in comparison with type 1 diabetes.

These multiple factors that might influence a relationship between dementia and type 2 diabetes as well as differences in populations and inclusion criteria likely contribute to the conflicting epidemiological data in this field. Some studies suggest that the prevalence of Alzheimer disease is increased in type 2 diabetes,[58,59,60] whereas in others, it has been reported as decreased[61,62,63,64,65,66] or comparable.[48,49,67,68,69,70,71] A confounding factor in these studies (including the current one) is that Alzheimer disease is often accompanied by a decreased BMI presumed to be a result of decreased food intake. Because the most potent risk factor for development of type 2 diabetes is an increased BMI, it is possible that an association between these conditions has been obscured by the relative protective effect of a decreased BMI in Alzheimer disease. Alternatively, it is possible that people with Alzheimer disease exercise less and therefore have decreased insulin sensitivity and increased risk for type 2 diabetes. As type 2 diabetes tends to develop at a younger age than Alzheimer disease and is associated with a decreased life expectancy, early death from complications of diabetes might obscure subsequent development of Alzheimer disease. The current pathology studies are unique inasmuch as the Alzheimer disease and non-Alzheimer disease groups were fully characterized both in life and by autopsy, and so although the numbers are small, it is provocative that there is a distinct increase in risk of islet amyloid in patients with Alzheimer disease despite a lower BMI. The clinical data (protocols 1 and 2) are also community-based cases that have been defined extensively with respect to the presence or absence of dementia and followed over a relatively long term.[33] It is of interest that a population-based study from the same region showed an association between type 2 diabetes and Alzheimer disease.[59] Whereas the former study examined records of all known cases of type 2 diabetes in the Rochester area at the time of the study for a diagnosis of dementia and Alzheimer disease (1,455 cases), the present study was focused on a much smaller cohort of patients with Alzheimer disease (100 cases) and control subjects (138 cases) enrolled in the ADPR,[33] wherein the diagnosis of Alzheimer disease was rigorously established, and then the same patients were followed annually in the study thereafter and when deceased were included in the autopsy studies. One other factor that might have caused discrepancies between reported studies is the changing definition of diabetes. The present study uses the criteria adopted for FPG concentrations in 1997 by an expert committee convened by the American Diabetes Association.[72] As a consequence of this report, the plasma glucose concentration required to establish the diagnosis of diabetes was decreased from 140 mg/dl to 126 mg/dl. Furthermore, a high-risk group was established for the subsequent development of diabetes with an FPG concentration of 110-125 mg/dl. Studies that used the higher values for diagnosis of diabetes would report lower prevalence rates in both Alzheimer disease and control subjects and possibly not observe differences between groups that might be evident with the criteria used here.

Another potential confounding factor in previous as well as the present studies is recruitment bias. All studies performed at major tertiary referral centers such as the Mayo Clinic are subject to such bias. Efforts were made to minimize this in the present clinical studies by recruitment of patients from the local community from the community clinics of the Mayo Medical Center. Patients were therefore attending the Mayo Clinic community clinics for primary care when they were recruited for either the Alzheimer disease or control groups of the clinical studies. Nonetheless, other recruitment bias may be introduced in a study such as ours by the failure of affected patients to seek medical care and therefore be unavailable for consideration. In the present study, there is a greater proportion of women than men in the clinical studies, which might be in part a reflection of recruitment bias but also potentially be due to the shorter life span of men than women once Alzheimer disease is diagnosed. Autopsy studies of Alzheimer disease cases and control subjects (for islet amyloid) would be subject to the same ascertainment bias as the ADPR since the cases were in the ADPR until death. In autopsy studies of type 2 diabetes cases versus control subjects for brain amyloid, we sought to minimize deliberate bias by including most recent autopsies in reverse sequence from cases that were appropriate for inclusion for these criteria. People who have an autopsy are of course in themselves a subgroup of the general population, so bias has to be considered. Notwithstanding these limitations, we do have the opportunity of presenting autopsy data from cases that were well characterized in life compared with most autopsy studies.

In conclusion, we report that there is an increased prevalence of both type 2 diabetes and IFG in a community cohort of patients with Alzheimer disease followed in Olmsted County, Rochester, Minnesota. We also report increased islet amyloid in patients with Alzheimer disease compared with control subjects. However, we did not observe an increased frequency of brain amyloid in cases of type 2 diabetes, although in cases of type 2 diabetes that did have brain amyloid, the extent of this amyloid increased with longer duration of diabetes, a correlate that did not extend to the age of patients with type 2 diabetes. Taken together, these clinical and pathological studies support a possible link between the neurodegenerative processes that lead to loss of cortical brain cells in Alzheimer disease and the loss of β-cells in type 2 diabetes.


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