Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function

Arvanitakis, Zoe; Wilson, Robert S.; Bienias, Julia L.; Evans, Denis A.; Bennett, David A.

doi:10.1001/archneur.61.5.661

Cited by 1,056 publications

(690 citation statements)

References 39 publications

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“…As glucose utilisation reflects neuronal activity in normal, resting physiological conditions [15,34], this finding prompts the question of the effects of thiazolidinediones on brain function. This issue is of current interest since (1) several million diabetic patients take pioglitazone, (2) these patients suffer from a greater rate of cognitive decline [27,28], and (3) pioglitazone is being tested for the treatment of neurological diseases (for information about clinical trials in progress see [6]). Below we discuss the possible mechanisms underlying the changes in brain glucose utilisation induced by pioglitazone in vivo, compared with the effects in cultured cells, and the therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary results consistently suggest that restoring adequate levels of insulin and glucose by using a thiazolidinedione facilitates memory in patients with Alzheimer's disease [26]. Since type 2 diabetes increases the risk of Alzheimer's disease and causes cognitive decline [27,28], facilitated glucose utilisation in the brain would provide additional therapeutic benefits to patients taking thiazolidinediones regularly to treat diabetes.…”

Section: Introductionmentioning

confidence: 95%

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Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

2006

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Aims/hypothesis Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. Materials and methods The regional pattern of CGU was measured with the 2-deoxy [ 14 C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor β1 (TGFβ1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months.Results Measurement of CGU in 27 brain regions confirmed that TGFβ1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFβ1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFβ1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. Conclusions/interpretation In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

2006

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“…In community-based studies among the general population, older age, female gender, low education, race and ethnicity, diabetes, hypertension, lipids, stroke, anemia, history of head trauma, mid-life obesity, inflammatory factors, the APOE4 allele and other genetic markers have been identified as risk factors for Alzheimer's disease or vascular cognitive impairment in community-based studies of the general community population (17)(18)(19)(20)(21)(22)(23). Dietary intake (fruits, vegetables, Omega 3's, Mediterranean diet) and physical activity appear to be protective, and hormone replacement therapy and homocysteine are still controversial; there is also an interactive effect between some risk factors and the APOE-4 allele (24).…”

Section: Risk Factors For Cognitive Impairment In Hemodialysis Patientsmentioning

confidence: 99%

Cognitive Impairment in the Aging Dialysis and Chronic Kidney Disease Populations: An Occult Burden

Murray

2008

Advances in Chronic Kidney Disease

335

236

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The heavy burden of cognitive impairment in hemodialysis and chronic kidney disease patients has only recently become recognized. Up to 70 percent of hemodialysis patients ages 55 years and older have moderate to severe chronic cognitive impairment, yet it is largely undiagnosed. Recent studies describe the strong graded relation between estimated glomerular filtration rate (eGFR) and cognitive function in CKD patients. The process of conventional hemodialysis may induce recurrent episodes of acute cerebral ischemia, which in turn may contribute to acute decline in cognitive function during dialysis. Thus the worst time to communicate with dialysis patients may be during the hemodialysis session. Both symptomatic and occult, subclinical ischemic cerebrovascular disease appear to play a large role in a proposed model of accelerated vascular cognitive impairment in these populations. Severe cognitive impairment or dementia among hemodialysis patients is associated with an approximately two-fold increased risk of both mortality and dialysis withdrawal. Pre-dialysis cognitive screening and adding dementia to the list of comorbidities on Form 2728 would provide critical information regarding the benefit versus risks of receiving dialysis. It could also improve quality of care and outcomes by raising clinician's awareness of the potential effects of cognitive impairment on medication, fluid, and dietary compliance, and ability to make advance directive decisions among dialysis patients. While much remains to be learned regarding the pathophysiology of cognitive impairment in kidney disease, the public health implications of this substantial burden are immediate.

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“…Type II diabetes (T2D) has been consistently associated with increased risk of cognitive decline (Arvanitakis, Wilson, Bienias, Evans, & Bennett, 2004), mild cognitive impairment (MCI) (Luchsinger et al, 2007) and dementia (Schnaider Beeri et al, 2004), both vascular dementia and AD (Peila, Rodriguez, & Launer, 2002). Of the shared features of AD and T2D, a major contributing factor to AD etiology is insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

et al. 2018

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Type 2 diabetes (T2D) is associated with increased risk of Alzheimer's disease (AD). There is evidence for impaired blood–brain barrier (BBB) in both diseases, but its role in the interplay between them is not clear. Here, we investigated the effects of high‐fat diet (HFD), a model for T2D, on the Tg2576 mouse model of AD, in regard to BBB function. We showed that HFD mice had higher weight, more insulin resistance, and higher serum HDL cholesterol levels, primarily in Tg2576 mice, which also had higher brain lipids content. In terms of behavior, Tg2576 HFD mice were less active and more anxious, but had better learning in the Morris Water Maze compared to Tg2576 on regular diet. HFD had no effect on the level of amyloid beta 1–42 in the cortex of Tg2576 mice, but increased the transcription level of insulin receptor in the hippocampus. Tg2576 mice on regular diet demonstrated more BBB disruption at 8 and 12 months accompanied by larger lateral ventricles volume in contrast to Tg2576 HFD mice, whose BBB leakage and ventricular volume were similar to wild‐type (WT) mice. Our results suggest that in AD, HFD may promote better cognitive function through improvements of BBB function and of brain atrophy but not of amyloid beta levels. Lipid metabolism in the CNS and peripheral tissues and brain insulin signaling may underlie this protection.

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Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function

Abstract: Diabetes mellitus may be associated with an increased risk of developing AD and may affect cognitive systems differentially.

Cited by 1,056 publications

References 39 publications

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

Cognitive Impairment in the Aging Dialysis and Chronic Kidney Disease Populations: An Occult Burden

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

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