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Diabetes mellitus and the risk of dementia
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The Rotterdam Study
Neurology 1999;53:1937
A. Ott, MD, PhD, R. P. Stolk, MD, PhD, F. van Harskamp, MD, H. A. P. Pols, MD, PhD, A. Hofman, MD, PhD and M. M. B. Breteler, MD, PhD
From the Departments of Epidemiology & Biostatistics (Drs. Ott, Stolk, Hofman, and Breteler), Medical Microbiology (Dr. Ott), Neurology (Dr. van Harskamp), and Internal Medicine III, Erasmus University Medical School (Dr. Pols), Rotterdam; and Julius Centre for Patient Oriented Research (Dr. Stolk), Utrecht University, Utrecht, the Netherlands.
Introduction
As type 2 diabetes mellitus is a risk factor for stroke,1,2 it is assumed to be linked with vascular dementia.3 In patients with multi-infarct dementia the prevalence of diabetes is indeed higher than expected.4,5 Persons with stroke appeared at greater risk of subsequent dementia if they had diabetes.6 The relation between diabetes and AD is less clear. Previous case-control studies reported relatively low rates of diabetes in patients with AD.4,5,7,8 In population-based prevalence studies, however, a positive association was found.9,10 Two cohort studies also detected increased AD incidence rates in diabetic patients.11,12 Recently discovered links between type 2 diabetes and AD are indications of advanced glycation end-products (AGE) and increased AGE receptor expression in brains of patients with AD.13,14 As AGEs are involved in diabetes complications,15 diabetes might influence AD brain pathology.
ABSTRACT
OBJECTIVE: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD.
BACKGROUND: Both dementia and diabetes are frequent disorders in elderly people.
METHODS: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders.
RESULTS: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). This finding may reflect greater risk of dementia in more severe diabetes.
CONCLUSION: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
Results.
At baseline, 692 (10.9%) of the 6,370 study participants had diabetes mellitus, of whom 390 (56.4%) did not use antidiabetes medication or were newly diagnosed, 232 (33.5%) used oral medication, and 70 (10.1%) were treated with insulin. Among those using insulin therapy, there were no insulin-dependent diabetes mellitus patients. Diabetes prevalence increased with age. Adjusting for age there was no difference in diabetes rates between men and women (table 1). Except for education and atrial fibrillation all possible confounding variables differed significantly between persons with and without diabetes mellitus.
Duration of follow-up ranged from 4 days to 6 years; quartiles were 1.5, 1.9, and 2.5 years, and average follow-up was 2.1 years. During the follow-up period, 126 (2.0%) participants became demented. Of those 89 (70.6%) were diagnosed with AD (13 with coexistent cerebrovascular disease), 18 (14.3%) were classified into vascular dementia, and 19 (15.1%) had another type of dementia. Duration of follow-up did not differ between dementia subtypes. Dementia patients were significantly older than those who were nondemented (table 2). There was no difference in dementia risk by gender. The age- and sex-adjusted diabetes prevalence was significantly higher in persons who developed dementia as compared to nondemented.
Diabetes mellitus almost doubled the risk of dementia (age- and sex-adjusted relative risk (RR) 1.9, 95% CI 1.3 to 2.8, table 3). A comparable result was obtained when analyses were restricted to those in whom the diagnosis was made by reviewing medical files (adjusted RR 1.7, 95% CI 0.8 to 3.7). Relative risks were similar for men (RR 1.8, 95% CI 0.8 to 4.1) and women (RR 1.9, 95% CI 1.2 to 3.0). We observed no clear modification in diabetes related dementia risk by age. Relative risks were 2.0 for those younger than 75 years, 2.2 in those 75 to 84 years, 1.4 in persons aged 85 and older.
The risk of incident dementia was clearly modified by baseline treatment (see table 3), with the lowest relative risk in newly discovered or untreated diabetic patients (RR 1.3, 95% CI 0.7 to 2.3) and the highest RR among patients treated with insulin (RR 4.3, 95% CI 1.7 to 10.5). In 298 of the 390 (76%) diabetic patients without medication at baseline, diabetes treatment at follow-up was known. Of these, 227 (76%) did not use antidiabetes medication, 67 (22%) used oral medication, and 4 (1%) insulin. The latter 71 diabetes patients were not at increased risk of dementia (RR 0.8, 95% CI 0.1 to 5.6).
Additional adjustment for possible confounders or intermediates, even when all were added to the regression model, gave a maximum decrease of the RR of 0.2 while remaining significant. Diabetes increased the risk of both AD and vascular dementia (table 4). If analysis was limited to patients who underwent neuroimaging, the relative risk for AD was 2.3 (95% CI 0.96 to 5.5). Additional adjustments for confounders again did not result in substantial changes of the estimates.
In this population, the fraction of incident dementia attributable to diabetes mellitus (population attributable risk) was 8.8%; 8.1% in men and 9.2% in women.
Discussion.
In this large prospective study of dementia, persons with diabetes mellitus were at increased risk of dementia, including AD, particularly if they were treated with insulin. These results confirm our previous cross-sectional findings of an association of type 2 diabetes with dementia and AD.9
Major advantages of the Rotterdam Study to investigate risk factors of dementia are the size of the study, the longitudinal and population-based design, and the fact that exposure and most of disease status were defined by active in-person examination. Presence of diabetes was assessed before onset of dementia, which prevented ascertainment bias. Selection bias was minimized by the population-based design and because follow-up of the population at risk of dementia was complete. However, not all participants could be rescreened in person and this may have led to selective underdiagnosis of dementia in this part of the population. Still, we found a similar elevated risk among diabetes patients in whom the dementia diagnosis was made by reviewing their medical files.
A limitation of the current study is that brain imaging could not be obtained of all dementia patients and we may have underestimated cerebrovascular pathology in demented persons. Although increased relative risks of AD by diabetes were not different in patients for whom brain imaging was available as compared to those without MRI, it remains possible that unrecognized strokes are involved in the association we found.
Previous cross-sectional studies have shown positive associations of diabetes with vascular dementia, but an inverse relation with AD.4,5,7,8 However, these studies were based on selected patients and controls. The presence of diabetes was assessed from medical records and not actually screened for. Furthermore, in these studies, patients with indicators of vascular or cerebrovascular disease were mostly excluded from the AD group, thereby obstructing the possibility to study these factors, and thus diabetes mellitus, in relation to AD. Only two prior longitudinal studies on the risk for dementia by diabetes have been published.11,12 In these studies, the relative risk of AD by diabetes is of the same magnitude as in our study: RR 2.2 (95% CI 0.97 to 4.9) in the prospective Hisayama study, which had a longer follow-up period but included fewer participants (n = 828).11 In the Rochester study, which was retrospective and register-based, RR were 2.3 (95% CI 1.6 to 3.3) for men and 1.4 (95% CI 0.9 to 2.0) for women.12
The relation between diabetes mellitus and dementia could either be explained through vascular disease or by nonvascular effects of diabetes. Diabetes mellitus is notorious for micro- and macrovascular complications.28 It is a well-known risk factor for strokes,1,2 which, if they accumulate or strike vital brain segments, may cause dementia.25 An increased risk of vascular dementia by diabetes is to be expected.
Our finding with respect to AD is less evident. One explanation for this finding would be that we misdiagnosed patients with dementia due to vascular causes as AD, although this would require a considerable number of wrongly subtyped patients to get the substantial RR we found. It may also be that the syndrome, defined by the currently accepted AD criteria,25 indeed has a vascular connection. The notion of vascular involvement in the pathogenesis of AD is growing.25,29,30 Our finding of a high RR for AD with cerebrovascular disease points toward a second possible explanation: silent cerebral infarcts may have uncovered imminent AD. Even in those we diagnosed as having AD only, silent strokes may have contributed to the dementia. These small infarctions, which tend to occur deep in the brain and cause no neurologic symptoms, are hard to diagnose without pathology. In conflict with our findings, a recent retrospective postmortem study found no difference between 49 patients with diabetes and 52 age- and sex-matched controls with respect to Alzheimer-type brain pathology.31 In another recent study, however, an association was found between features of the insulin resistance syndrome and AD, which may support our findings.10
There are several arguments to consider the possibility that other than vascular factors may contribute to dementia in diabetic patients. In our study the limited effect of adjustment for vascular risk indicators supports a nonvascular pathway. Previous studies have reported nonvascular functional and structural changes in the CNS of diabetic patients.32,33 Also, diabetic patients without clinical cerebrovascular disease34,35 were found to perform significantly poorer on cognitive tests than healthy controls. Recently, advanced glycation end-products (AGE), which are the result of nonenzymatic glycosylation of proteins,36 were found in plaques and tangles of Alzheimer brains, even in early stages of disease.13 Excessive AGE formation by chronic hyperglycemia may play a role in long-term diabetic complications.15 In brains of AD patients the receptor for AGE appears overexpressed,14 and this receptor is activated by β-amyloid, which is involved in Alzheimer pathology.37 Activation of this receptor leads to increased oxidative stress that may result in cellular damage.29
In both this and our previous study we found the strongest association between diabetes and AD for patients who at baseline were on insulin treatment.9 This finding may reflect greater risk of dementia in more severe diabetes. Patients on insulin treatment may have more severe diabetes, or a longer history of diabetes, and are thus longer exposed to diabetes related risk factors. Leibson et al., however, found no effect of diabetes duration on dementia risk.11 Direct or indirect effects of insulin could contribute to the risk of dementia. Hypoglycemic episodes frequently complicate insulin treatment,38 and contrary to hyperglycemia, hypoglycemia can cause irreversible brain damage.32,33
The almost doubled risk of dementia in diabetic patients implies that diabetes may play a role in the pathogenesis of dementia in a considerable proportion of all dementia patients. Further studies to unravel the underlying mechanisms are required.
Methods.
Study population. The Rotterdam Study is a community-based prospective cohort study in which chronic disorders of the elderly are investigated.16 The study was approved by the Medical Ethics Committee of Erasmus University. Participants gave written informed consent and permission to retrieve information from treating physicians.
The study was carried out in a suburb of Rotterdam, the Netherlands. The eligible population (n = 10275) consisted of all persons aged 55 years and older living in this suburb, and included people living in institutions. Baseline examinations took place from 1990 to mid 1993 and included 7,983 participants. During baseline, 7,528 (94%) were screened for dementia, which resulted in 474 patients with dementia.17 Exclusion of these, and eight undetermined cases, resulted in a cohort of 7,046 persons at risk for dementia.
Diabetes examinations were not performed in the first 433 persons who entered the study, and were missing in 243 persons due to logistic reasons. This left 6,370 persons to be included in the current study.
Follow-up examinations took place from September1993 to the end of 1994. In this period, 5,232 (82%) participants were re-examined for dementia. During the follow-up period, 330 (5%) had died, and 808 (13%) refused examinations or were too ill. Of the 1,138 persons who were not re-examined, information on dementia status was obtained through general practitioners and medical records.
Diabetes and other baseline measurements. Medication use by participants was assessed during the initial home interview. Of institutionalized participants, medication was reported by the medical staff. Blood was drawn by venipuncture to assess nonfasting serum glucose levels. Participants who did not use antidiabetes medication received a glucose drink of 75 g in 200 mL water. Two hours later a second blood sample was obtained to measure postload serum glucose. Diabetes mellitus was defined according to World Health Organization criteria for epidemiologic studies of diabetes: use of antidiabetes medication or a random or postload serum glucose greater than 11 mmol/L.18 Unfortunately, no reliable estimate was made of disease duration in patients with diabetes.
We measured the following variables to test for possible confounding: educational background, assessed during the initial interview, was dichotomized in less than 7 years of schooling or more. Weight and height (measured with indoor clothing, without shoes) were used to calculate body mass index, expressed in kg/m2. The ratio between waist and hip circumference was used as a measure of body fat distribution. Smoking habits at baseline were categorized into never, past, and current smoking. Alcohol consumption was assessed in a semiquantitative food frequency questionnaire and expressed in grams pure alcohol per day. Systolic blood pressure was measured in supine position with a random zero sphygmomanometer. Hypertension was defined as a systolic blood pressure of 160 or above, a diastolic blood pressure of 95 or above, or use of antihypertensive drugs. The systolic blood pressure ratio of the ankle over the upper arm (ankle-to-brachial index) was used as a measure of peripheral atherosclerosis.19 We assessed presence of atrial fibrillation and of probable or definite myocardial infarction by computer software on resting ECG.20 Stroke history was assessed during the baseline interview. Strokes were recorded only if documented in medical records, which were verified by a neurologist.
Dementia case-finding. Both at baseline and follow-up, dementia was diagnosed with a similar three step protocol, consisting of a screening test (combined Mini-Mental State Examination21 and Geriatric Mental State schedule,22 organic level), further testing of screenpositives, and a diagnostic workup.17,23 Brain NMR (MRI) scans were not part of the core protocol of the Rotterdam Study, but we tried to obtain neuroimaging in persons suspected of dementia. MRI scans were obtained in one quarter of the dementia patients. In addition to active screening, during the entire follow-up period, general practitioners of participants reported incident cognitive disorders. We also closely cooperated with the regional institute for outpatient mental health care, which is responsible for dementia care facilities and nursing home indications. Of interval cases reported with memory problems or dementia and of subjects who could not be re-examined in person (due to death or refusal), we studied medical files. Thus we obtained complete follow-up of the population at risk.
A panel consisting of a neurologist, neuropsychologist, and the study physician reviewed all existing information to make a diagnosis of dementia. Diagnostic criteria for AD were from the National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association24 and for vascular dementia from the National Institute of Neurologic Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences.25 As proposed in the latter criteria, we recognized an Alzheimer's subgroup with cerebrovascular disease. For other dementias, criteria from the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) were used.26
Data analysis. Means and proportions of baseline characteristics were compared for persons with and without diabetes mellitus. Age- and sex-adjusted differences were calculated with logistic regression analyses for dichotomous variables and with linear regression for continuous variables.
The relative risk of dementia by diabetes was calculated with a Cox proportional hazard regression model, with duration of follow-up as the time-to-event variable. Age at baseline and duration of follow-up were calculated in days and converted into years with two decimals. The age at dementia onset was taken to be the midpoint between baseline age and age at diagnosis.23 To adjust for age, both linear and squared age were entered in the models. Sex was added to the model if analyses included both men and women. Our cross-sectional data suggested modification by sex in the relation between diabetes and dementia.9 Therefore we examined if gender or age modified the relation by calculating relative risks by sex category, and in strata of age (below 75, 75 to 85, and 85 years and older). To check if associations could be attributed to confounding, analyses were repeated with possible confounders added to the models. Some variables could in fact be intermediates of the relation between diabetes and dementia. In that case, adding them to the regression model will lead to disappearance of the association.
We finally assessed which proportion of dementia cases was attributable to diabetes, or factors associated with diabetes, as described by Levin.27 This population attributable risk (PAR) was calculated using the formula
PAR= [(RR-1)PF]PF/[1+(RR-1)PF]
in which RR is the adjusted relative risk and PF the population fraction with diabetes.
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