Hyperinsulinemia and risk of Alzheimer disease

Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Joseph P. Mailman School of Public Health, Columbia University, New York, USA.
Neurology (Impact Factor: 8.29). 11/2004; 63(7):1187-92. DOI: 10.1212/01.WNL.0000140292.04932.87
Source: PubMed


To explore the association between fasting insulin levels and dementia.
Fasting insulin levels were measured from frozen sera using solid-phase chemiluminescent enzyme immunoassay in a sample of elderly subjects chosen at random from a cohort of persons aged 65 years and older from northern Manhattan. Dementia was diagnosed using standard methods. Neuropsychiatric testing was available on all subjects at each follow-up interval.
A total of 683 subjects without prevalent dementia were followed for 3,691 person-years and 149 persons developed dementia (137 Alzheimer disease [AD], 6 dementia associated with stroke, 6 other). The risk of AD doubled in the 39% of the sample with hyperinsulinemia (HR = 2.1; 95% CI: 1.5, 2.9) and was highest in people without diabetes. The HR relating presence of hyperinsulinemia or diabetes in 50% of our sample to AD was 2.2 (95% CI: 1.5, 3.1). The risk of AD attributable to the presence of hyperinsulinemia or diabetes was 39%. The HR of AD for the highest quartile of insulin compared to the lowest was 1.7 (95% CI: 1.0, 2.7; p for trend = 0.009). Hyperinsulinemia was also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains.
Hyperinsulinemia is associated with a higher risk of AD and decline in memory.

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    • ". Large-scale population based prospective studies have shown that type 2 diabetes increases the risk of late-onset AD, and different studies have calculated the RR varying from 1.44 to 1.9 [81] [82] [83] [84]. Another population based follow up study showed that hyperinsulinemia or type 2 diabetes increases the risk of of AD with a hazard ratio of 2.2 [85]. A mean follow-up study of 5.5 years for a population of 1138 persons has shown that diabetes is a strong risk factor for AD (hazard ratio 2.4) and the risk is further augmented when other risk factors like hypertension, heart disease and smoking are simultaneously present [86]. "
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    ABSTRACT: Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.
    Aging and Disease 08/2015; 6(4):282-99. DOI:10.14336/AD.2014.002 · 3.07 Impact Factor
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    • "On the other hand, AD pathology may cause vascular injury, as when A␤-induced inflammation damages the endothelium. The vast majority of AD cases are sporadic and the ultimate neurotoxic mechanisms have not been elucidated, however it seems that type 2 diabetes (T2D) may play a relevant role in the development of AD (Ott et al., 1996; Luchsinger et al., 2004; Plastino et al., 2010). Some relevant links between T2D and AD include the following: Impaired insulin secretion and resistance, as well as glucose intolerance seem to be associated with increased risk of AD (Ott et al., 1996; Ott et al., 1999; Plastino et al., 2010). "
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    ABSTRACT: Aging remains the main risk factor to suffer Alzheimer's disease (AD), though epidemiological studies also support that type 2 diabetes (T2D) is a major contributor. In order to explore the close relationship between both pathologies we have developed an animal model presenting both AD and T2D, by crossing APP/PS1 mice (AD model) with db/db mice (T2D model). We traced metabolic and cognitive evolution before T2D or AD pathology is present (4 weeks of age), when T2D has debuted but no senile plaques are present (14 weeks of age) and when both pathologies are well established (26 weeks of age). APP/PS1xdb/db mice showed an age-dependent synergistic effect between T2D and AD. Significant brain atrophy and tau pathology were detected in the cortex by 14 weeks, that spread to the hippocampus by 26 weeks of age. Severe cognitive impairment was also detected as soon as at 14 weeks of age. Interestingly, in APP/PS1xdb/db mice we observed a shift in Aβ soluble/insoluble levels, and whereas more toxic soluble species were favoured, senile plaques (SP) were reduced. An overall increase of microglia activation was observed in APP/PS1xdb/db mice. We also found exacerbated hemorrhagic burden in APP/PS1xdbd/db mice, suggesting that blood brain barrier alterations may be responsible for the early pathological features observed. Moreover, metabolic parameters can predict many of these alterations, supporting a role for T2D in AD pathology. This new model provides a relevant tool to further explore the relationship between T2D, AD and vascular implications, offering the possibility to assess therapeutic approaches, that by improving T2D metabolic control could delay or prevent AD pathology. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 07/2015; 62:69-79. DOI:10.1016/j.psyneuen.2015.07.606 · 4.94 Impact Factor
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    • "Type 2 diabetes has been identified as a risk factor for Alzheimer's disease [25] [31], presumably linked to an impairment in insulin signalling in the brain. In the brains of people with Alzheimer's disease, insulin signalling was found to be much impaired, even independently of a medical history of diabetes [29] [44]. "
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    ABSTRACT: Type 2 diabetes is a risk factor for Alzheimer's disease (AD). Previously, we have shown that the diabetes drug liraglutide is protective in middle aged and in old APP/PS1 mice. Here, we show that liraglutide has prophylactic properties. When injecting liraglutide once-daily ip. in two months old mice for 8 months, the main hallmarks of AD were much reduced. Memory formation in object recognition and Morris water maze were normalised and synapse loss and the loss of synaptic plasticity was prevented. In addition, amyloid plaque load, including dense core congophilic plaques, was much reduced. Chronic inflammation (activated microglia) was also reduced in the cortex, and neurogenesis was enhanced in the dentate gyrus. The results demonstrate that liraglutide may protect from progressive neurodegeneration that develops in AD. The drug is currently in clinical trials in patients with AD. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 07/2015; 293. DOI:10.1016/j.bbr.2015.07.024 · 3.03 Impact Factor
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