Insulin resistance is associated with the pathology of Alzheimer disease

Matsuzaki, Takashi; Sasaki, Kenji; Tanizaki, Yumihiro; Hata, Jun; Fujimi, Kouhei; Matsui, Yukiko; Sekita, Atsuko; Suzuki, Satoshi; Kanba, Shigenobu; Kiyohara, Yutaka; Iwaki, Toru

doi:10.1212/wnl.0b013e3181eee25f

Cited by 383 publications

(267 citation statements)

References 35 publications

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“…These hypotheses are also supported by our previous reports from the cohort and clinicopathological studies that demonstrated that elevated 2-h PG levels were significantly associated with increased risks of development of Alzheimer disease (8) and the formation of neuritic plaques (9). For the other potential mechanisms, diabetes may cause brain atrophy as a result of microvascular ischemic disease (2) or elevated cortisol levels by the impaired feedback mechanism in the hypothalamicpituitary-adrenal axis (23).…”

Section: Discussionsupporting

confidence: 76%

“…The Hisayama Study is a populationbased prospective study of cerebro-and cardiovascular diseases and dementia in a general Japanese population. Using the data from the Hisayama Study, we previously observed that diabetes and elevated 2-h postload glucose (PG) concentrations were significantly associated with the development of Alzheimer disease (8) and neuritic plaque formation (9). The current study was conducted to investigate the association between diabetes-related parameters and brain and hippocampal atrophy, using MRI scans in elderly residents of Hisayama, Japan.…”

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confidence: 99%

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Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study

et al. 2016

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OBJECTIVETo investigate the association between diabetes and brain or hippocampal atrophy in an elderly population. RESEARCH DESIGN AND METHODSA total of 1,238 community-dwelling Japanese subjects aged ‡65 years underwent brain MRI scans and a comprehensive health examination in 2012. Total brain volume (TBV), intracranial volume (ICV), and hippocampal volume (HV) were measured using MRI scans for each subject. We examined the associations between diabetes-related parameters and the ratios of TBV to ICV (an indicator of global brain atrophy), HV to ICV (an indicator of hippocampal atrophy), and HV to TBV (an indicator of hippocampal atrophy beyond global brain atrophy) after adjustment for other potential confounders. RESULTSThe multivariable-adjusted mean values of the TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios were significantly lower in the subjects with diabetes compared with those without diabetes (77.6% vs. 78.2% for the TBV-to-ICV ratio, 0.513% vs. 0.529% for the HV-to-ICV ratio, and 0.660% vs. 0.676% for the HV-to-TBV ratio; all P < 0.01). These three ratios decreased significantly with elevated 2-h postload glucose (PG) levels (all P for trend <0.05) but not fasting plasma glucose levels. Longer duration of diabetes was significantly associated with lower TBV-to-ICV, HV-to-ICV, and HV-to-TBV ratios. The subjects with diabetes diagnosed in midlife had significantly lower HV-to-ICV and HV-to-TBV ratios than those without and those diagnosed in late life. CONCLUSIONSOur data suggest that a longer duration of diabetes and elevated 2-h PG levels, a marker of postprandial hyperglycemia, are risk factors for brain atrophy, particularly hippocampal atrophy.

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Section: Discussionsupporting

confidence: 76%

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confidence: 99%

Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study

et al. 2016

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“…Importantly, impaired metabolic parameters, such as hyperglycemia and hyperinsulinemia, positively correlate with development of AD-related pathology (8,9). Elevated blood glucose levels increase the hazard risk of dementia in both diabetic and nondiabetic individuals (by 40 and 18%, respectively) (4) and are associated with cognitive decline and reduced hippocampal volume (10).…”

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confidence: 99%

Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease

2014

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A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.

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“…Although insulin mitigates Aβ deposition and hyperphosphorylation of tau [17,31], DM in combination with ApoE ε4 may lead to excessive phosphorylation of tau [32], but only in subjects with late stage AD [21]. DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms [31].…”

Section: Dmt2: Type 2 Diabetes Mellitus; Mci: Mild Cognitive Impairmentmentioning

confidence: 99%

The Diabetic Brain and Dementia

Jellinger¹

2015

J Alzheimers Dis Parkinsonism

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Alzheimer's Disease (AD) and Diabetes Mellitus (DM) are the two most common and devastating health problems in the elderly. They share a number of common features among which are important impact on quality of life and substantial health care costs. Epidemiological and biological evidence support a pathophysiological link between Type 2 Diabetes Mellitus (DMT2) and cognitive impairment [1][2][3]. A causative association between DM and Alzheimer's disease has been suggested on the basis of clinical, epidemiological, genetic and experimental studies [2,[4][5][6][7][8][9]. Persons with DM have a higher incidence of cognitive decline and an increased risk of developing AD and other types of dementia, and comorbidity increases the risk [10,11]. Insulin resistance predicts medial temporal hypermetabolism in Mild Cognitive Impairment (MCI) conversion to AD [12] and glucose uptake changes in AD in medial temporal regions predicting worse memory performance [13]. DM has been shown to influence the rate of functional decline among patients with mild AD dementia than in those without comorbid DM [14]. However, the precise mechanisms involved in the development of AD in diabetics are not yet fully understood, and several pathogenic pathways have been discussed [3,4,[15][16][17][18][19][20].Autopsy studies stated that diabetic patients show significantly less AD pathology (senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, etc.) but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM [5,[21][22][23][24][25][26][27]. Vasculo-neural dysfunction has been suggested to represent a potential etiological linkage between DMT2 and AD [6,28], while others suggested that the association between DM and dementia is only partially mediated through cerebrovascular disease and that DM is associated independently with overal dementia among elderly, but not with AD or vascular dementia [29].Positive DMT2 status appears to exacerbate AD pathology in the presence of ApoE ε4 [30]. Although insulin mitigates Aβ deposition and hyperphosphorylation of tau [17,31], DM in combination with ApoE ε4 may lead to excessive phosphorylation of tau [32], but only in subjects with late stage AD [21]. DM modifies metabolism of Aβ and tau causing Aβ/tau-dependent pathological changes, although there is evidence that suggests an interaction of Aβ/tau-dependent and -independent mechanisms [31]. Evidence supports insulin's role in cognition, synaptic remodelling and facilitation of memory [33]. On the other hand, insulin has been shown to modulate the level of Aβ, to protect neurons against detrimental effects of Aβ on synapses [33]. It further facilitates reduction of amyloid plaques, downregulation of Aβ-derived diffusible ligand-binding sites and also to promote tau hypophosphorylation, which stabilizes microtubules. These data and the observation that the combination of insulin and other antidiabetic medication is associated with lower neuritic plaque density [23,34] are providing a...

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Insulin resistance is associated with the pathology of Alzheimer disease

Abstract: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon4.

Cited by 383 publications

References 35 publications

Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study

Association Between Diabetes and Hippocampal Atrophy in Elderly Japanese: The Hisayama Study

Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease

The Diabetic Brain and Dementia

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