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Long-term use of metformin and Alzheimer’s disease: beneficial or detrimental effects

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Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by extracellular deposition of amyloid beta (Aβ) leading to cognitive decline. Evidence from epidemiological studies has shown the association between type 2 diabetes mellitus (T2DM) and the development of AD. T2DM and peripheral insulin resistance (IR) augment the risk of AD with the development of brain IR with inhibition of neuronal insulin receptors. These changes impair clearance of Aβ, increase secretion of Aβ1-42, reduce brain glucose metabolism, and abnormal deposition of Aβ plaques. Insulin-sensitizing drug metformin inhibits aggregation of Aβ by increasing the activity of the insulin-degrading enzyme (IDE) and neprilysin (NEP) levels. Additionally, different studies raised conflicting evidence concerning long-term metformin therapy in T2DM patients, as it may increase the risk of AD or it may prevent the progression of AD. Therefore, the objective of this review was to clarify the beneficial and detrimental effects of long-term metformin therapy in T2DM patients and risk of AD. Evidence from clinical trial studies revealed the little effect of metformin on AD. Various animal studies showed that metformin increases Aβ formation by activation of amyloid precursor protein (APP)-cleaving enzymes with the generation of insoluble tau species. Of note, the metformin effect on cognitive function relative to AD pathogenesis is mostly assessed in animal model studies. The duration of metformin therapy was short in most animal studies, this finding cannot apply to the long-term duration of metformin in humans. Therefore, large-scale prospective and comparative studies involving long-term metformin therapy in both diabetic and non-diabetic patients are required to exclude the effect of T2DM-induced AD.

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Medicine, Medical Faculty, College of Medicine, Al-Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq

    Hayder M. Al-kuraishy & Ali I. Al-Gareeb

  2. Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, 51744, Egypt

    Hebatallah M. Saad

  3. Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt

    Gaber El-Saber Batiha

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  1. Hayder M. Al-kuraishy
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  2. Ali I. Al-Gareeb
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  4. Gaber El-Saber Batiha
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HMA-K and AIA conceptualized the manuscript, wrote, edited and reviewed the main text and approved the final edition of the manuscript. HMS and GE-SB prepared the figures, wrote, corrected, amended and approved the final edition of the manuscript.

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Al-kuraishy, H.M., Al-Gareeb, A.I., Saad, H.M. et al. Long-term use of metformin and Alzheimer’s disease: beneficial or detrimental effects. Inflammopharmacol 31, 1107–1115 (2023). https://doi.org/10.1007/s10787-023-01163-7

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