Mechanistic insight into the role of metformin in Alzheimer's disease

Sanati, Mehdi; Aminyavari, Samaneh; Afshari, Amir R.; Sahebkar, Amirhossein

doi:10.1016/j.lfs.2021.120299

Cited by 29 publications

(13 citation statements)

References 153 publications

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“…In this regard, our findings may recall the recent theory of a neurobiological link between AD and insulin resistance, showing overlapping brain abnormalities between the 2 conditions ( Abbatecola et al, 2006 ; Rizzo et al, 2010 ; Lynn et al, 2022 ). However, in our sample of T2DM patients, the potential effect of metformin, anti-diabetic drug counteracting insulin resistance, hypothesized to limit neurodegenerative changes of the brain ( Sanati et al, 2022 ) was not confirmed, considering that no significant differences in NVC abnormalities were found by comparing drug-naïve patients to those taking metformin, most likely due to the fact that the latter subgroup included both a small patients number and patients who had started the pharmacological therapy since less than 6 months.…”

Section: Discussionmentioning

confidence: 84%

“…Particularly, it has been observed that T2DM may accelerate the effects of aging on some brain structures, as a form of neurodegeneration, and may therefore contribute to the higher prevalence of cognitive impairment observed in T2DM patients ( Abbatecola et al, 2006 ; Rizzo et al, 2010 ; Riederer et al, 2017 ). Emerging evidence indicates that insulin resistance and hyperinsulinemia are shared features between T2DM and Alzheimer’s disease (AD), suggesting a potential counteracting role of some antidiabetic drugs ( Rizzo et al, 2014 , 2022 ), such as also metformin, on several neurodegenerative mechanisms ( Sanati et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Neurovascular coupling in patients with type 2 diabetes mellitus

Canna

Esposito

Tedeschi

et al. 2022

Front. Aging Neurosci.

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Functional and metabolic neural changes in Type 2 diabetes mellitus (T2DM) can be associated with poor cognitive performances. Here we analyzed the functional-metabolic neurovascular coupling (NVC) in the brain of T2DM patients. Thirty-three patients (70 ± 6 years, 15 males) with recent T2DM diagnosis and 18 healthy control (HC) subjects (65 ± 9 years, 9 males) were enrolled in a brain MRI study to identify the potential effects of T2DM on NVC. T2DM patients were either drug-naive (n = 19) or under treatment with metformin (n = 14) since less than 6 months. Arterial spin labeling and blood oxygen level dependent resting-state functional MRI (RS-fMRI) images were combined to derive NVC measures in brain regions and large-scale networks in a standard brain parcelation. Altered NVC values in T2DM patients were correlated with cognitive performances spanning several neurological domains using Spearman correlation coefficients. Compared to HC, T2DM patients had reduced NVC in the default mode network (DMN) and increased NVC in three regions of the dorsal (DAN) and salience-ventral (SVAN) attention networks. NVC abnormalities in DAN and SVAN were associated with reduced visuo-spatial cognitive performances. A spatial pattern of NVC reduction in the DMN, accompanied by isolated regional NVC increases in DAN and SVAN, could reflect the emergence of (defective) compensatory processes in T2DM patients in response to altered neurovascular conditions. Overall, this pattern is reminiscent of neural abnormalities previously observed in Alzheimer’s disease, suggesting that similar neurobiological mechanisms, secondary to insulin resistance and manifesting as NVC alterations, might be developing in T2DM pathology.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Neurovascular coupling in patients with type 2 diabetes mellitus

Canna

Esposito

Tedeschi

et al. 2022

Front. Aging Neurosci.

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“…The largest group of drugs tested in phase 3 of AD drug development consists of disease-modifying small molecules [ 105 ], which include substances modulating (i) metabolism and bioenergetics, e.g., metformin [ 354 , 355 ], semaglutide [ 356 ], and tricaprylin [ 357 , 358 ]; (ii) oxidative stress and blood flow in the brain, e.g., omega-3 polyunsaturated fatty acids [ 359 ] and ethyl eicosapentaenoate (icosapent ethyl) [ 360 ]; (iii) synaptic plasticity and neuroprotection, e.g., blarcamesine [ 361 , 362 ], atuzaginstat [ 363 ], AGB101 (levetiracetam) [ 364 , 365 ], and simufilam [ 366 ]; (iv) Aβ pathology, e.g., ALZ-801 (valiltramiprosate), an oral prodrug of homotaurine that blocks the formation of toxic Aβ oligomers [ 334 , 367 , 368 ]; (v) neuroinflammation, e.g., NE3107 [ 369 ] and curcumin [ 337 , 370 , 371 , 372 , 373 ]; and more. Disease-modifying drugs are also the monoclonal antibodies directed at Aβ; besides aducanumab [ 374 ] it is also gantenerumab [ 374 , 375 ], lecanemab [ 375 ], donanemab [ 376 ], and solanezumab [ 374 , 377 ], which have shown some efficiency and are tested in phase 3 clinical trials [ 317 ].…”

Section: Alzheimer’s Drugsmentioning

confidence: 99%

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Fišar

2022

Biomolecules

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Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

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“…Traditionally, metformin’s principal mechanisms were understood to be suppression of hepatic gluconeogenesis and enhancement of peripheral insulin sensitivity via AMPK activation 6. However, it also exhibits pleiotropic effects including modifying the gut microbiome, immune function and inflammatory mechanisms, which could plausibly modify the pathogenesis of dementia in diabetes 7 8…”

Section: Introductionmentioning

confidence: 99%

Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records

Doran,

Tunnicliffe,

Muzambi

et al. 2024

BMJ Open Diab Res Care

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Introduction4.2 million individuals in the UK have type 2 diabetes, a known risk factor for dementia and mild cognitive impairment (MCI). Diabetes treatment may modify this association, but existing evidence is conflicting. We therefore aimed to assess the association between metformin therapy and risk of incident all-cause dementia or MCI compared with other oral glucose-lowering therapies (GLTs).Research design and methodsWe conducted an observational cohort study using the Clinical Practice Research Datalink among UK adults diagnosed with diabetes at ≥40 years between 1990 and 2019. We used an active comparator new user design to compare risks of dementia and MCI among individuals initially prescribed metformin versus an alternative oral GLT using Cox proportional hazards regression controlling for sociodemographic, lifestyle and clinical confounders. We assessed for interaction by age and sex. Sensitivity analyses included an as-treated analysis to mitigate potential exposure misclassification.ResultsWe included 211 396 individuals (median age 63 years; 42.8% female), of whom 179 333 (84.8%) initiated on metformin therapy. Over median follow-up of 5.4 years, metformin use was associated with a lower risk of dementia (adjusted HR (aHR) 0.86 (95% CI 0.79 to 0.94)) and MCI (aHR 0.92 (95% CI 0.86 to 0.99)). Metformin users aged under 80 years had a lower dementia risk (aHR 0.77 (95% CI 0.68 to 0.85)), which was not observed for those aged ≥80 years (aHR 0.95 (95% CI 0.87 to 1.05)). There was no interaction with sex. The as-treated analysis showed a reduced effect size compared with the main analysis (aHR 0.90 (95% CI 0.83 to 0.98)).ConclusionsMetformin use was associated with lower risks of incident dementia and MCI compared with alternative GLT among UK adults with diabetes. While our findings are consistent with a neuroprotective effect of metformin against dementia, further research is needed to reduce risks of confounding by indication and assess causality.

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Mechanistic insight into the role of metformin in Alzheimer's disease

Cited by 29 publications

References 153 publications

Neurovascular coupling in patients with type 2 diabetes mellitus

Neurovascular coupling in patients with type 2 diabetes mellitus

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Incident dementia risk among patients with type 2 diabetes receiving metformin versus alternative oral glucose-lowering therapy: an observational cohort study using UK primary healthcare records

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