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

Abstract and Introduction

Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid β protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively. Given these similarities, we questioned whether there may be a common underlying mechanism predisposing to islet and cerebral amyloid. To address this, we first examined the prevalence of type 2 diabetes in a community-based controlled study, the Mayo Clinic Alzheimer Disease Patient Registry (ADPR), which follows patients with Alzheimer disease versus control subjects without Alzheimer disease. In addition to this clinical study, we performed a pathological study of autopsy cases from this same community to determine whether there is an increased prevalence of islet amyloid in patients with Alzheimer disease and increased prevalence of cerebral amyloid in patients with type 2 diabetes. Patients who were enrolled in the ADPR (Alzheimer disease n = 100, non-Alzheimer disease control subjects n = 138) were classified according to fasting glucose concentration (FPG) as nondiabetic (FPG <110 mg/dl), impaired fasting glucose (IFG, FPG 110-125 mg/dl), and type 2 diabetes (FPG >126 mg/dl). The mean slope of FPG over 10 years in each case was also compared between Alzheimer disease and non-Alzheimer disease control subjects. Pancreas and brain were examined from autopsy specimens obtained from 105 humans (first, 28 cases of Alzheimer disease disease vs. 21 non-Alzheimer disease control subjects and, second, 35 subjects with type 2 diabetes vs. 21 non-type 2 diabetes control subjects) for the presence of islet and brain amyloid. Both type 2 diabetes (35% vs. 18%; P < 0.05) and IFG (46% vs. 24%; P < 0.01) were more prevalent in Alzheimer disease versus non-Alzheimer disease control subjects, so 81% of cases of Alzheimer disease had either type 2 diabetes or IFG. The slope of increase of FPG with age over 10 years was also greater in Alzheimer disease than non-Alzheimer disease control subjects (P < 0.01). Islet amyloid was more frequent (P < 0.05) and extensive (P < 0.05) in patients with Alzheimer disease than in non-Alzheimer disease control subjects. However, diffuse and neuritic plaques were not more common in type 2 diabetes than in control subjects. In cases of type 2 diabetes when they were present, the duration of type 2 diabetes correlated with the density of diffuse (P < 0.001) and neuritic plaques (P < 0.01). In this community cohort from southeast Minnesota, type 2 diabetes and IFG are more common in patients with Alzheimer disease than in control subjects, as is the pathological hallmark of type 2 diabetes, islet amyloid. However, there was no increase in brain plaque formation in cases of type 2 diabetes, although when it was present, it correlated in extent with duration of diabetes. These data support the hypothesis that patients with Alzheimer disease are more vulnerable to type 2 diabetes and the possibility of linkage between the processes responsible for loss of brain cells and β-cells in these diseases.

The islet of Langerhans in type 2 diabetes is characterized by β-cell loss[1,2] and islet amyloid derived from islet amyloid polypeptide (IAPP),[3,4,5] a protein coexpressed and secreted with insulin by β-cells. Brain dysfunction in Alzheimer disease is characterized by loss of neocortical neurons[6] and focal amyloid deposits, which consist of the locally expressed amyloid β protein (AβP).[7,8,9,10,11,12,13] The prevalence of both Alzheimer disease and type 2 diabetes increases with age, and both have genetic components.[14,15,16,17,18,19]

AβP and IAPP both spontaneously form into amyloid aggregates in an aqueous environment.[7,8,20,21] The role of these aggregates of IAPP and AβP in β-cell and cortical neuronal death in type 2 diabetes and Alzheimer disease is controversial. Small amyloid aggregates of either of these proteins are cytotoxic.[22,23,24,25] The mechanism of the cytotoxicity mediated by small protein aggregates has been hypothesized to be by induction of membrane damage.[25,26,27] In the case of IAPP, evidence exists to suggest that abnormal aggregation occurs initially intracellularly, and after cell death, IAPP-derived fibrils accumulate extracellularly.[24,28,29] Similar mechanisms are also possible in Alzheimer disease. In vivo, even though IAPP and AβP are present in an aqueous environment, in health neither protein forms fibrils, suggesting that mechanisms exist to prevent this otherwise spontaneous process. These mechanisms likely include the chaperone protein pathway, a system for protein trafficking via intracellular binding proteins (chaperone proteins), which bind nascent proteins and facilitate their transport within the cell.[30]

We have previously hypothesized that IAPP amyloid formation in type 2 diabetes may occur under circumstances of genetic variance, which results in a relative decreased affinity of the chaperone protein pathway for trafficking of IAPP.[31] It is plausible that a low affinity for binding by one or more chaperone proteins to IAPP may be shared with a similar low affinity for binding to AβP. In support of this hypothesis, Schwartz[32] suggested that there might be a relationship between amyloid deposits in the brain and pancreatic islets.

We used both clinical studies (in living patients and community-based control subjects) and pathological studies to examine the existence of a shared risk for Alzheimer disease and type 2 diabetes. In the clinical studies, we took advantage of a unique community-based (Olmsted County, MN) cohort of well-characterized patients with Alzheimer disease and control subjects without Alzheimer disease[33] to address the question, "Is type 2 diabetes more common in Alzheimer disease?" In the pathology studies, we studied brain and pancreas in autopsy cases from the same community to address the hypotheses 1) that islet amyloid is more frequent in patients with Alzheimer disease than in control subjects without Alzheimer disease and 2) that amyloid deposits are more common in the brain in patients with type 2 diabetes than in nondiabetic humans.


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