Metformin, Other Antidiabetic Drugs, and Risk of Alzheimer's Disease: A Population‐Based Case–Control Study

Imfeld, Patrick; Bodmer, Michael; Jick, Susan S.; Meier, Christoph

doi:10.1111/j.1532-5415.2012.03916.x

Cited by 337 publications

(261 citation statements)

References 32 publications

(53 reference statements)

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“…Metformin protects against neurological complications of type 2 diabetes mellitus, including cognitive impairment and cerebral vascular disease [263]. Recently, metformin has been used in a clinical trial for AD, and it is reported that this drug can produce beneficial effects in AD patients [264]. When administered with insulin, metformin provides significant neuroprotection in that A␤PP-A␤ levels including A␤PP-A␤ neuritic plaques, and oligomeric A␤PP-A␤-mediated downregulation of the insulin receptor are reduced [265].…”

Section: Metformin (Fig 3)mentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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Section: Metformin (Fig 3)mentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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“…This links into the emerging hypothesis that AD should be classed as a third type of diabetes (115,116). However, reports are conflicting as to its effectiveness as a therapeutic intervention and the risk of developing AD (117,118). This may underlie the fact that the extent of metformin's molecular pharmacology is still under investigation (31,119,120).…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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“…A case-control study based in the United Kingdom suggested that metformin may be associated with an increased risk of AD in longterm use [84], and treatment of mice with metformin has been shown to increase tau protein aggregation [85]. However, the same study does also show metformin to reduce tau phosphorylation, leading to the authors concluding that the benefits are mitigated by negative effects, rather than metformin having an overall detrimental effect [85].…”

Section: Metforminmentioning

confidence: 78%

Parkinson';s Disease, Diabetes and Cognitive Impairment

Ashraghi¹,

Pagano²,

Polychronis³

et al. 2016

EMI

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Patents published in the last 5 years could be used in novel approaches to Parkinson's treatment by targeting specific pathophysiology proteins, such as Nurr1, PINK1 and NrF2, while patents to improve penetration of the blood brain barrier could allow improved efficacy of existing treatments. Conclusion:Further studies using GLP-1 agonists and DPP-4 inhibitors to treat PD are warranted as they have shown promise.

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Metformin, Other Antidiabetic Drugs, and Risk of Alzheimer's Disease: A Population‐Based Case–Control Study

Abstract: Long-term use of sulfonylureas, thiazolidinediones, or insulin was not associated with an altered risk of developing AD. There was a suggestion of a slightly higher risk of AD in long-term users of metformin.

Cited by 337 publications

References 32 publications

Slow Excitotoxicity in Alzheimer's Disease

Slow Excitotoxicity in Alzheimer's Disease

Astrocytic transporters in Alzheimer's disease

Parkinson';s Disease, Diabetes and Cognitive Impairment

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