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      Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline

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          Abstract

          In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer’s disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.

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          Most cited references102

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          Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study

          Aim: To estimate the prevalence of Alzheimer’s disease (AD) and other dementias in the USA using a nationally representative sample. Methods: The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. Results: The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71–79 years to 37.4% of those aged 90 and older. Conclusions: Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.
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            Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.

            A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.
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              An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

              Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                01 September 2015
                September 2015
                : 7
                : 9
                : 7332-7357
                Affiliations
                Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University, 2213 Garland Ave., Nashville, TN 37232, USA
                Author notes
                [* ]Authors to whom correspondence should be addressed; E-Mails: Jennifer.m.walker@ 123456vanderbilt.edu (J.M.W.), Fiona.harrison@ 123456vanderbilt.edu (F.E.H.); Tel.: +1-615-875-6182 (J.M.W.), +1-615-875-5547 (F.E.H.); Fax: +1-615-936-1667 (F.E.H.).
                Article
                nutrients-07-05341
                10.3390/nu7095341
                4586536
                26340637
                0a9d4a34-a2a0-4686-ad82-c3d737929629
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 April 2015
                : 21 August 2015
                Categories
                Review

                Nutrition & Dietetics
                alzheimer’s disease,type 2 diabetes mellitus,high fat diets,obesity,insulin resistance,inflammation,diet reversal,animal models,humans,cognition

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