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Diabetes, Alzheimer disease, and vascular dementia: Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality - pdf attached
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A population-based neuropathologic study
S. Ahtiluoto, MD, T. Polvikoski, MD, PhD, M. Peltonen, PhD, A. Solomon, MD, PhD, J. Tuomilehto, MD, MA, PhD, B. Winblad, MD, PhD, R. Sulkava, MD, PhD and M. Kivipelto, MD, PhD
Published online before print August 25, 2010 Neurology 2010
From Jules: Diabetes and its precursor insulin resistance IS a major concern for patients aging with HIV. It has been established in studies in HIV-negatives that diabetes and likely also insulin resistance can lead to premature neurological diseases including alzheimer's, reduced cognitive function and dementia. This study reports that the mechanism that causes this appears to be damage to the vascular system, the system of arteries and blood flow throughout the body & the brain too. This is concerning because previous studies in HIV have found HIV+ individuals have accelerated aging to their vascular system, so this is one of the concerns we also have among others, regarding the aging problem. It is likely that insulin resistance is a major contributor to vascular aging, and to inflammation, and should be a major part of new research
"Our results suggest that the relation between diabetes and clinical AD diagnosis may not be fully explained by an increase in AD-type neuropathology. Instead, it is more likely that diabetic elderly people develop more extensive microvascular pathology, which alone or together with AD-type pathology, particularly in APOE {epsilon}4 carriers, results in an increased risk of clinical dementia. The neuropathologic processes leading to dementia among elderly patients with diabetes as well as the role of insulin resistance in the diabetes-dementia association need to be further clarified."
From the Department of Chronic Disease Prevention (S.A., M.P.), National Institute for Health and Welfare, Helsinki, Finland; Institute for Ageing and Health (T.P.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (A.S., M.K.), University of Kuopio, Finland; Karolinska Institutet Alzheimer's Disease Research Center (A.S., M.K., B.W.), Department of Neurobiology, Care Sciences and Society, Huddinge, Stockholm, Sweden; Department of Public Health (J.T.), University of Helsinki, South Ostrobothnia Central Hospital, SeinŠjoki; and Division of Geriatrics (R.S.), School of Public Health and Clinical Nutrition, University of Kuopio, Kuopio, Finland.
ABSTRACT
Objective: To investigate the relation of diabetes to dementia, Alzheimer disease (AD), and vascular dementia (VaD), through analyses of incidence, mortality, and neuropathologic outcomes in a prospective population-based study of the oldest old.
Methods: The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ³85 years on April 1, 1991. Survivors were reexamined in 1994, 1996, 1999, and 2001. Autopsies were performed in 291 persons who died during the follow-up (48% of total population). Diabetes was assessed according to self-report, medical record of physician-diagnosed diabetes, or use of antidiabetic medication. Macroscopic infarcts were identified from 1-cm coronal slices of cerebral hemispheres, 5-mm transverse brainstem slices, and sagittal cerebellum slices. Methenamine silver staining was used for β-amyloid, methenamine silver-Bodian staining for neurofibrillary tangles, and modified Bielschowsky method for neuritic plaques. Cox proportional hazards and multiple logistic regression models were used to analyze the association of diabetes with dementia and neuropathology, respectively.
Results: Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality. Individuals with diabetes were less likely to have β-amyloid (hazard ratio [HR] [95% confidence interval (CI)] was 0.48 [0.23-0.98]) and tangles (HR [95% CI] 0.72 [0.39-1.33]) but more likely to have cerebral infarcts (HR [95% CI] 1.88 [1.06-3.34]) after all adjustments.
Conclusion: Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE {epsilon}4 carriers) results in increased dementia risk.
Abbreviations: AD = Alzheimer disease; CI = confidence interval; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; HR = hazard ratio; NFT = neurofibrillary tangles; OR = odds ratio; VaD = vascular dementia.
Population-based longitudinal studies have shown that diabetes is an independent risk factor for dementia1 and its main subtypes Alzheimer disease (AD)1-3 and vascular dementia (VaD),3-5 but also controversial findings have been reported.6,7 Some biologic mechanisms have been postulated through which diabetes might increase the risk of AD: vascular mechanisms, toxic effects of hyperglycemia, insulin resistance of the brain, formation of advanced glycation end products, and competition for insulin-degrading enzyme resulting in reduced degradation of β-amyloid, but none of these has been proven unequivocally. As diabetes is known to increase cerebrovascular disease,8 its association to VaD is understandable. Several studies have reported a greater risk and faster rate of cognitive decline in patients with type 2 diabetes.9,10 Amyloid plaques and neurofibrillary tangles (NFT) are the neuropathologic hallmarks of AD. Evaluating differences in quantity of these outcomes between diabetic and nondiabetic subjects might shed light on the mechanisms behind the epidemiologic connections reported. Patients with AD and diabetes have a markedly higher mortality when compared to nondiabetic patients with AD.11 The aim of this study was to investigate the associations of diabetes with dementia and its main subtypes through analyses of incidence, mortality, and neuropathologic outcomes in a prospective population-based study of people aged at least 85 years.
DISCUSSION
This population-based clinical-pathologic study of the oldest old found that diabetes doubled dementia incidence and increased mortality and risk of cerebral infarctions, but was related to less amyloid accumulation. These results suggest that the increased dementia incidence in very elderly diabetic patients might not primarily be explained by an increase in AD-type neuropathology, but rather by an increase in vascular brain pathology. Cerebrovascular lesions are known to play an important role in determining the presence and severity of the clinical symptoms of AD.23 Fewer AD neuropathologic lesions are needed to produce dementia in people who also have cerebrovascular lesions.23
In our study, dementia duration was shorter in diabetic compared to nondiabetic people (probably due to the diabetes-related increase in mortality), but this was insufficient to fully explain group differences in neuropathology. Also, controlling or stratifying analyses for dementia status did not change the patterns of association between diabetes and neuropathology. Clinical dementia diagnoses correlated well with brain autopsy findings, which reduces the probability of misclassification of dementia cases. However, current diagnostic criteria for dementia are known to have a bias toward AD24 and AD diagnostic criteria do not acknowledge the contribution of vascular pathology, particularly small cerebrovascular lesions.
An earlier study in younger elderly found a similar negative association between diabetes and AD neuropathology, reporting that persons with diabetes had fewer NPs and NFTs in the cerebral cortex and lower plaque ratings in the hippocampus compared to persons without diabetes.25 In another study, dementia was associated with greater amyloid load and free radical damage in nondiabetic persons, but with microvascular infarcts and neuroinflammation in diabetic patients.26 Four other studies found no relation between diabetes and AD neuropathology.27-30 A positive association was reported only in one study where people with both diabetes and the APOE {epsilon}4 allele had higher numbers of hippocampal NPs and hippocampal and cortical NFTs.2 Differences in results between studies could be due to methodologic and population differences. Age is particularly important, as the association between AD pathology and dementia is stronger in younger old compared to older old persons.31 The rise in NP and NFT densities seen in people who are 60 to 80 years old and transition from normal cognition to dementia is not observed in nonagenarians and centenarians with similar levels of dementia.32 Previous studies on diabetes and neuropathology included subjects up to 86 years old at the time of death, while the average age at death in the Vantaa 85+ autopsy population was over 91 years.
Even in this very old population, carrying even one APOE {epsilon}4 allele increased the risk of dementia, AD, and VaD. APOE {epsilon}4 was also associated with increased risk of β-amyloid and NFTs. Diabetic patients with APOE {epsilon}4 had a significantly increased incidence of dementia, AD, and VaD compared with diabetic patients without APOE {epsilon}4, but no significant interactions between APOE {epsilon}4 and diabetes were found regarding dementia incidence or neuropathologic outcomes. It has, however, been previously reported that having both diabetes and the APOE {epsilon}4 allele can increase AD risk to a greater extent than the sum of each risk factor would lead to expect,33 i.e., that they might operate synergistically for AD.
The major strength of this study is its prospective population-based design and relatively large sample size. The entire Vantaa 85+ study population comprised 98% of the people aged 85 years or above living in a geographically well-defined area, and the autopsy rate was also high, 48%. Quantitative, systematic methods were used to identify AD pathology. Diagnosis of diabetes was obtained from several sources and the longitudinal nature of the study ensured that those with severe forms of diabetes were included in analyses.
Among limitations, no biochemistry was used to identify diabetes and no data on diabetes duration, glycemic control, or insulin levels were available. Thus, the effect of diabetes severity could not be assessed. There may have been several people with undiagnosed diabetes in the group classified as nondiabetic which might have contributed to the negative association reported in the neuropathologic part of the study. Earlier studies have reported that both borderline and uncontrolled diabetes also increase the risk of AD.34 Immunohistochemical methods are currently available for investigating β-amyloid; however, only conventional neuropathology methods were available at the time of this study.
The results of this study are in line with earlier findings in younger elderly populations that diabetes and APOE {epsilon}4 carrier status increase the risk of dementia, and extend this observation to the very elderly population. Our results suggest that the relation between diabetes and clinical AD diagnosis may not be fully explained by an increase in AD-type neuropathology. Instead, it is more likely that diabetic elderly people develop more extensive microvascular pathology, which alone or together with AD-type pathology, particularly in APOE {epsilon}4 carriers, results in an increased risk of clinical dementia. The neuropathologic processes leading to dementia among elderly patients with diabetes as well as the role of insulin resistance in the diabetes-dementia association need to be further clarified.
RESULTS
Population characteristics. Formation of the study population is shown in figure 1 and demographic and clinical characteristics in table 1. Of the 588 persons included in this study, 79.6% were female, 22.3% had diabetes, and 39.6% had dementia at baseline. Diabetic patients compared with nondiabetic people more often had heart failure (78.6% vs 57.1%, p < 0.001) and hypertension (33.9% vs 23.4%, p = 0.028) at baseline but there were no significant differences between groups regarding other cardiovascular risk factors or conditions.
Diabetes and dementia. In cross-sectional analyses at baseline, diabetes was not related to dementia, AD, or VaD after adjusting for gender, age, education, cardiovascular conditions, and APOE {epsilon}4. No significant interactions between APOE {epsilon}4 and diabetes were found for prevalent dementia.
Incidence of dementia in people free of dementia at baseline (n = 355) was twice as high in diabetic then nondiabetic people even after adjustments for age, gender, education, and APOE {epsilon}4 status (table 2). Gender-stratified analyses showed higher incidence of dementia in diabetic compared to nondiabetic women: adjusted HR (95% confidence interval [CI]) 2.31 (1.43-3.71) but not men: 1.11 (0.28-4.33). However, the small number of men makes it difficult to draw conclusions on gender differences. In people carrying the APOE {epsilon}4 allele, dementia incidence was nearly 4 times higher in diabetic compared to nondiabetic persons even after adjustments for age, gender, and education (figure 2). Diabetic compared to nondiabetic subjects had twice as high incidence of both AD (adjusted HR [95% CI] 2.45 [1.33-4.53]) and VaD (2.15 [1.06-4.36]) after all adjustments.
Diabetes and mortality. In the entire population, diabetic patients compared with nondiabetic people had increased mortality: HR (95% CI) was 1.30 (1.07-1.59). In stratified analyses by dementia status, diabetes increased mortality in people without dementia: HR (95% CI) 1.38 (1.07-1.77) but not significantly for patients with dementia: HR (95% CI) 1.21 (0.85-1.71).
Diabetes and neuropathology. In neuropathologic analyses, the proportion of individuals with β-amyloid and NFTs was lower in diabetic compared to nondiabetic people; for β-amyloid, this difference was significant (table 3). The proportion of individuals with cerebral infarctions was significantly higher in diabetic compared to nondiabetic people. Individuals with diabetes were less likely to have β-amyloid and NFTs but more likely to have cerebral infarcts after adjustments for age at death, gender, education, APOE {epsilon}4, and dementia status. Stratified analyses by dementia status showed similar patterns of association for diabetes: in persons without dementia, adjusted ORs (95% CI) were 0.68 (0.24-1.91) for amyloid, 0.44 (0.16-1.19) for NFTs, and 3.27 (1.14-9.33) for cerebral infarcts (table e-1 on the Neurology¨ Web site at www.neurology.org). In patients clinically diagnosed with AD, adjusted ORs (95% CI) were 0.04 (0.00-0.41) for amyloid, 0.76 (0.18-3.21) for NFTs, and 0.59 (0.17-2.10) for cerebral infarcts, as expected due to AD criteria excluding significant vascular disease (table e-2).
Carrying at least one APOE {epsilon}4 allele increased the risk of β-amyloid and NFTs, but not cerebral infarcts. No significant interactions were found between diabetes and APOE {epsilon}4 in relation to neuropathologic outcomes. People with a longer duration of dementia were more likely to have β-amyloid, but adding duration of dementia into the model did not change the diabetes-β-amyloid relation. Duration of dementia was not a significant predictor for presence of NFTs or cerebral infarcts.
Findings of β-amyloid at brain autopsy were related to the clinical AD diagnosis: odds ratio (OR) (95% CI) 3.48 (1.19-10.18), and all dementia: 3.12 (1.48-6.57), but not VaD: 1.28 (0.56-2.94). NFTs at autopsy were related to clinical diagnoses: for AD: OR (95% CI) 2.91 (1.41-6.01), all dementia: 1.92 (1.06-3.47), and VaD: 0.86 (0.44-1.69). Cerebral infarcts were associated with clinical VaD diagnosis: OR (95% CI) 2.26 (1.19-4.27) and all dementia: 1.78 (1.01-3.15), but not AD: 1.01 (0.55-1.85).
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