Diabetes, Alzheimer disease, and vascular dementia: A population-based neuropathologic study

Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Neurology (Impact Factor: 8.3). 09/2010; 75(13):1195-202. DOI: 10.1212/WNL.0b013e3181f4d7f8
Source: PubMed

ABSTRACT 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.
The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ≥85 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.
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.
Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE ε4 carriers) results in increased dementia risk.

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Available from: Jaakko Tuomilehto, Sep 17, 2014
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    • "Neuropathological autopsy studies do not support that type 2 diabetes predisposes to development of AD pathology in the brain of aged persons when compared to age-matched controls [95]. Several epidemiological studies also have examined a proportion of their study cohorts at autopsy for neuropathological changes typical of AD and concluded that type 2 diabetes does not promote AD pathology in the brain and instead vascular pathologies in brain are more commonly associated with type 2 diabetes [89] [96]. While the controversy is persisting between epidemiological findings and neuropathological observations in relating type 2 with AD, in experimental AD research insulin and insulin resistance have been linked to AD pathogenesis in multiple ways. "
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    08/2015; 6(4):282-99. DOI:10.14336/AD.2014.002
    • "Metabolic abnormalities, such as reduced glucose utilization and energy dysmetabolism, are risk factors for cognitive impairment and AD (Hoyer 2004; Mazza et al. 2011; Messier 2005; Mosconi et al. 2008; de la Monte et al. 2006; Schubert 2005). Linkage between metabolic abnormalities and AD is supported by the increased risk of acquiring dementia and AD in individuals with diabetes mellitus and obesity (Xu et al. 2011; Sims-Robinson et al. 2010; Luchsinger et al. 2001; Ahtiluoto et al. 2010; Correia et al. 2011; Whitmer et al. 2005, 2008; Janson et al. 2004; Craft 2009). Diabetes mellitus has been shown to increase the conversion from mild cognitive impairment to AD (Li et al. 2011). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in the elderly. Accumulation of Aβ peptides in the brain has been suggested as the cause of AD (amyloid cascade hypothesis); however, the mechanism for the abnormal accumulation of Aβ in the brains of AD patients remains unclear. A plethora of evidence has emerged to support a link between metabolic disorders and AD. This study was designed to examine the relationship between energy status and Aβ production. Neuro 2a neuroblastoma cells overexpressing human amyloid precursor protein 695 (APP cells) were cultured in media containing different concentrations of glucose and agonist or antagonist of AMP-activated-protein-kinase (AMPK), a metabolic master sensor. The results showed that concentrations of glucose in the culture media were negatively associated with the activation statuses of AMPK in APP cells, but positively correlated with the levels of secreted Aβ. Modulating AMPK activities affected the production of Aβ. If APP cells were cultured in high glucose medium (i.e., AMPK was inactive), stimulation of AMPK activity decreased the production levels of Aβ. On the contrary, if APP cells were incubated in medium containing no glucose (i.e., AMPK was activated), inhibition of AMPK activity largely increased Aβ production. As AMPK activation is a common defect in metabolic abnormalities, our study supports the premise that metabolic disorders may aggravate AD pathogenesis.
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    • "However, in chronic conditions such as diabetes [58] [59] [60] [61], obesity [5] [16], and hypertension [62] [63], vasomotion appears to be depressed. Reports from longitudinal studies suggest that diabetes [64] [65] [66], untreated hypertension [67], and obesity at midlife [68] [69] [70], are associated with an increased risk of developing AD, supporting the hypothesis of an indirect link between depressed vasomotion and AD. However , the association between the above risk factors and AD remains controversial as other longitudinal studies have reported contrasting results [71] [72] [73] [74]. "
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