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

Research Design and Methods

The primary objective of the Mayo Clinic Alzheimer Disease Patient Registry (ADPR) was to acquire a cohort of patients with Alzheimer disease and matched non-Alzheimer disease control subjects for assessment of the progression of Alzheimer disease clinically with respect to imaging and other neurological studies. Patients who were from southeastern Minnesota and had dementia were identified at the time of routine general medical examination in the Department of Community Internal Medicine at the Mayo Clinic. All studies were approved by the Mayo Clinic Institutional Review Board. When there was a suspicion of Alzheimer disease during a routine periodic medical examination, a neurological evaluation that included the Mini-Mental State Exam, Geriatric Depression Scale, Hachinski Ischemic Scale, Short Test of Mental Status, Record of Independent Living, and extensive neuropsychological testing was performed.[33] Age- and sex-matched control subjects were randomly identified from the same community clinics. All enrolled cases had detailed evaluation to confirm or rule out (control subjects) Alzheimer disease. Once a patient had been enrolled in the ADPR as a case of Alzheimer disease or as a control, he or she was followed annually for clinical studies that included a fasting blood glucose measurement. Recruitment to the ADPR was haphazard (i.e., not deliberately biased) with respect to the presence or absence of diabetes or the blood glucose concentration. Exclusion criteria were 1) chronic treatment with glucocorticoids, 2) a history of pancreatitis, or 3) type 1 diabetes. The distinction between type 1 and type 2 diabetes was made on conventional clinical criteria. The features favoring type 1 diabetes included lean BMI (and further weight loss) and young age at onset, insulin requirement at onset, documented ketoacidosis, presence of other autoimmune diseases, and a family history of autoimmune disease. Features favoring type 2 diabetes included strong family history, prolonged insulin-independent treatment, obesity, absence of autoimmune diseases, and later age of onset. It is acknowledged that the distinction between type 1 and type 2 diabetes is not without error, but in view of the large number of cases in the present studies and the high prevalence of type 2 versus type 1 diabetes, it is unlikely that the conclusions of the present studies have been influenced by erroneous inclusion of cases of type 1 diabetes ( Table 1 ).

Protocol 1: is Type 2 Diabetes More Common in Alzheimer Disease? These recruitment criteria provided a total of 100 patients with Alzheimer disease and 138 non-Alzheimer disease control subjects. In protocol 1, these cases and control subjects were classified according to the criteria of the American Diabetes Association into one of three groups: nondiabetic (< 110 mg/dl), impaired fasting glucose (IFG; 110-125 mg/dl), and type 2 diabetes (>126 mg/dl) based on the most recent glucose concentration measurements. Individuals who were taking blood glucose-lowering treatment for diabetes were classified as type 2 diabetes regardless of their most recent fasting glucose concentration.

Protocol 2: is the Increase in Fasting Plasma Glucose With Age Greater in Alzheimer Disease? We also examined the changes in fasting plasma glucose (FPG) with aging in this cohort of patients. For each subject, we regressed the annual median FPG value against age. This was used to obtain a predicted FPG value for each subject at each decade and also to compare the slopes of the regression lines between groups (Alzheimer disease versus control subjects), using a two-sided rank sum test. To be included in this analysis, patients were required to have FPG values recorded that spanned at least 10 consecutive years from age 50 or greater and at least one value available for each calendar year. Ages of ≥50 years only were considered. These criteria resulted in a study population of 52 patients with Alzheimer disease and 105 non-Alzheimer disease control subjects.

Case Recruitment. Alzheimer disease patients (group 1) and control subjects (non-Alzheimer disease; group 2) had been enrolled in the Mayo Clinic ADPR study during life.[33] At death, non-Alzheimer disease and Alzheimer disease cases had an autopsy examination of the brain and the diagnosis of Alzheimer disease (or its absence) was confirmed using CERAD (Consortium to Establish a Registry for Alzheimer Disease) criteria.[34] In the pathology study, we include 1) only cases with clinically and pathologically confirmed Alzheimer disease or non-Alzheimer disease, 2) cases with an autopsy including both brain and pancreas, and 3) cases with FPG documented at the Mayo Clinic within 2 years (Alzheimer disease 100%, non-Alzheimer disease 100%) and in most cases 1 year (non-Alzheimer disease 100%, Alzheimer disease 89% of complete autopsies) of death. A mean FPG value for each subject was the mean of at least two independent measurements. Alzheimer disease patients were sex- and age-matched with control subjects during life as per the Mayo Clinic ADPR study and were still matched for age at death (84 ± 8 vs. 85 ± 4 years, Alzheimer disease vs. non-Alzheimer disease; P = 0.7). Alzheimer disease was diagnosed 5.5 ± 2.4 (range 1.3-9.9) years before death.

Type 2 diabetes cases (group 3; FPG >126 mg/dl) were identified via Mayo Clinic autopsy records. For inclusion they 1) had died in the 6 years preceding this study, 2) were also from Olmsted County, 3) had an autopsy including both brain and pancreas, and 4) had had a general medical examination performed including an FPG at Mayo Clinic during the year before death. Exclusion criteria included inadequate preservation of pancreatic tissue for anatomic study, type 1 diabetes, or secondary causes of diabetes. Diagnosis of diabetes in this cohort was 12 ± 9 years before death. These selection criteria yielded 35 cases, but the mean age at death was younger in type 2 diabetes than the in Alzheimer disease cases (73 ± 8 vs. 84 ± 8 years; P < 0.001). Therefore, identified from the Mayo Clinic autopsy records was an additional control group consisting of 21 cases (group 4) who were age, BMI, and sex matched with type 2 diabetic patients, had a normal FPG documented within 1 year before death, and were also meeting criteria 1-4 as for group 3. Groups 3 and 4 were included haphazardly (i.e., not consciously biased) with respect to the presence or absence of Alzheimer disease. The characteristics of each of these four study groups are summarized in Table 2 .

Protocol 3: is Islet Amyloid Increased in Patients With Alzheimer Disease? To address this question, we studied pancreas samples obtained at autopsy in 28 cases with Alzheimer disease and 21 without Alzheimer disease (groups 1 and 2 in Table 2 ). In addition, 35 cases with type 2 diabetes and 21 without type 2 diabetes were studied as a point of reference. Protocol 3 included a total of 105 cases.

Protocol 4: is Brain Amyloid More Common in Patients With Type 2 Diabetes? To address this question, we studied brain samples in 28 cases with and 19 without type 2 diabetes (groups 3 and 4 in Table 2 ). As a reference, 26 cases with Alzheimer disease and 19 without Alzheimer disease were studied. Some paraffin blocks of the superior/midfrontal gyrus were not available, resulting in 92 cases entering protocol 4.

Light Microscopy. Pancreas and brain samples were obtained at autopsy from the four groups described above. Slides were examined blinded to the identity of the case by light microscopy.

Pancreas. Sequential sections obtained from paraffin-embedded pancreas tail samples were stained with hematoxylin/eosin and Congo red and by immunostaining for insulin.[29] The nature of pink amyloid deposits in Congo red-stained slides was confirmed by green/orange birefringence under polarized light. At least 25 islets per specimen were scored for presence and extent of islet amyloid. The extent of amyloid deposition was classified per islet on a scale from 0 to 4, with 0 = no deposits, 1 = one deposit, 2 = a few small deposits, 3 = major deposition, and 4 = just a few endocrine cells left between confluent deposits.

Brain. Samples of the superior/midfrontal gyrus were collected, and the density of neuritic and diffuse plaques and neurofibrillary tangle (NFT) was determined. For visualizing neurofilaments, paraffin sections of the superior/midfrontal gyrus were stained with a modified Bielschowsky's technique. Per sample, the number of neuritic plaques, diffuse plagues, and NFT was determined in five microscope fields of 2 mm2 each.

Protocols 1 and 2. A rank sum test was used to compare age, and χ2 tests were used to compare number in groups according to classification for sex and diabetic, nondiabetic, or IFG status. A two-sided rank sum test was used to compare slope of fasting glucose versus age.

Protocols 3 and 4. An unpaired two-tailed Student's t test was used to compare age and BMI between groups. The nonparametric Mann-Whitney test was used to compare the frequency and extent of islet amyloid; FPG; and density of neuritic plaques, diffuse plagues, and NFT among groups. The χ2 test was used to compare the number of Alzheimer disease and non-Alzheimer disease subjects with type 2 diabetes. Spearman rank correlations were used to examine relationships among diffuse plagues, neuritic plaques, and NFT density versus duration of diabetes before death and age at death in type 2 diabetes.


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