# Long-term metformin use for Alzheimer's disease prevention?

Timothy Daly, Bruno P Imbimbo

► To cite this version:

Timothy Daly, Bruno P Imbimbo. Long-term metformin use for Alzheimer's disease prevention?. Alzheimer's & Dementia: the Journal of the Alzheimer's Association, 2025, 21 (4), pp.e70147. 10.1002/alz.70147. hal-05084523

HAL Id: hal-05084523

https://hal.science/hal-05084523v1

Submitted on 26 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Long-term metformin use for Alzheimer's disease prevention?

In *Alzheimer's & Dementia*, Zheng and colleagues published results from a UK-based cohort study of 210,237 participants, suggesting that metformin use reduced dementia risk beyond the level observed in patients with milder diabetes and better health profiles.¹

We build on the authors' observation that longer metformin treatment duration was associated with greater dementia risk reduction, along with evidence from epidemiology, the pathological mechanisms of Alzheimer's disease (AD), and metformin's availability, to propose that long-term metformin at 500 mg/day in high-risk individuals could serve as a preventive strategy to reduce the risk or delay the onset of AD and related dementias.

This approach is conceptually analogous to the well-established use of statins in cardiovascular medicine, where long-term administration in at-risk populations has been shown to reduce the incidence of major cardiovascular events.² We propose that long-term metformin use could be investigated as a repurposed drug for AD prevention.

Type 2 diabetes mellitus (T2DM) has shown a strong metabolic and inflammatory association with dementia.³ The study by Zheng et al.¹ is among a growing number of epidemiological studies reporting a protective effect of metformin on dementia risk, consistently indicating that longer metformin treatment duration is associated with greater risk reduction.⁴⁻⁶ Beyond epidemiological evidence, mechanistic insights also support the notion that metformin may exert neuroprotective effects through multiple pathways. These include not only its metabolic effects³ but also its role in attenuating general mechanisms of cellular aging,⁷ slowing brain aging,⁸ and modulating key AD-related pathologies, including amyloid and tau.⁹ Furthermore, metformin at 500 mg/day is the most widely prescribed antidiabetic drug worldwide, is recognized as an essential medicine by the World Health Organization as of 2023, and is available off-patent at low cost in most countries.¹⁰

Just as statins are prescribed to individuals with hyperlipidemia or other cardiovascular risk factors before the onset of overt disease,² metformin at 500 mg/day could be administered to individuals in the preclinical or prodromal stages of AD, such as older adults with mild cognitive impairment (MCI), insulin resistance, and/or a strong genetic predisposition (e.g., apolipoprotein E (APOE) ε4 homozygotes, pathogenic Sortilin-related Receptor 1 (SORL1) genetic variants, or individuals with a maternal history of AD). By targeting key pathways

involved in AD pathogenesis, metformin could potentially modify disease progression, making it a promising candidate for repurposing in the prevention of AD.

In conclusion, metformin is a safe, affordable, and widely used anti-T2DM drug, with growing evidence suggesting that its long-term use is associated with a lower risk of cognitive decline. An ongoing 18-month, double-blind, placebo-controlled trial—the Metformin in Alzheimer's Dementia Prevention study (NCT04098666)—is investigating the protective effects of doses up to 2000 mg/day, with results expected in 2027. Although this is an important study, it will not directly assess the therapeutic value of long-term use, which we consider the strongest argument for metformin in dementia risk reduction. Therefore, we advocate for a controlled, long-term intervention in high-risk individuals to provide high-level evidence on metformin's role in the prevention of AD and related disorders.

## ACKNOWLEDGMENTS

The authors have nothing to report.

## CONFLICT OF INTEREST STATEMENT

Dr. Timothy Daly has no conflicts of interest to declare. Dr. Bruno P. Imbimbo is an employee at Chiesi Farmaceutici. He is listed as an inventor in a number of Chiesi Farmaceutici's patents of anti-Alzheimer's drugs.

Author disclosures are available in the Supporting Information.

## FUNDING INFORMATION

Timothy Daly is a postdoctoral research fellow funded by the "Institut National de la Santé et de la Recherche Médicale" (INSERM) on the MEMENTO project (France).

Timothy Daly¹,²,³ ID

Bruno P. Imbimbo⁴

¹UMR 1219 Bordeaux Population Health, Université de Bordeaux & INSERM, Bordeaux, France

²UMR 5164, ImmunoConcept, University of Bordeaux & CNRS, Bordeaux, France

³Bioethics Program, FLACSO Argentina, Buenos Aires, Argentina

⁴Research & Development, Chiesi Farmaceutici, Parma, Italy

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2025 The Author(s). *Alzheimer's & Dementia* published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Correspondence

Timothy Daly, UMR 1219 Bordeaux Population Health, Université de
Bordeaux & INSERM, 146 rue Léo Saignat, 33076 Bordeaux, France.

Email: timothy.daly@u-bordeaux.fr

ORCID

Timothy Daly

<figure><img src="image_2.png" /></figure>

https://orcid.org/0000-0003-1650-242X

REFERENCES

1. Zheng B, Su B, Ahmadi-Abhari S, et al. Dementia risk in patients with type 2 diabetes: comparing metformin with no pharmacological treatment. *Alzheimers Dement*. 2023;19(12):5681-5689. doi:10.1002/alz.13349

2. US Preventive Services Task Force, Mangione CM, Barry MJ, Nicholson WK, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 2022;328(8):746-753. doi:10.1001/jama.2022.13044

3. Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. *Nat Rev Endocrinol*. 2018;14(10):591-604. doi:10.1038/s41574-018-0048-7

4. Tahmi M, Benitez R, Luchsinger JA. Metformin as a potential prevention strategy for Alzheimer's disease and Alzheimer's disease related dementias. *J Alzheimers Dis*. 2024;101(s1):S345-S356. doi:10.3233/JAD-240495

5. Sun M, Chen WM, Wu SY, Zhang J. Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction. *Brain*. 2024;147(4):1474-1482. doi:10.1093/brain/awad366

6. Tang C, Hao J, Tao F, Feng Q, Song Y, Zeng B. Association of metformin use with risk of dementia in patients with type 2 diabetes: a systematic review and meta-analysis. *Diabetes Obes Metab*. 2025;27:1992-2001. doi:10.1111/dom.16192

7. Kulkarni AS, Gubbi S, Barzilai N. Benefits of Metformin in attenuating the hallmarks of aging. *Cell Metab*. 2020;32(1):15-30. doi:10.1016/j.cmet.2020.04.001

8. Yang Y, Lu X, Liu N, et al. Metformin decelerates aging clock in male monkeys. *Cell*. 2024;187(22):6358-6378.e29. doi:10.1016/j.cell.2024.08.021

9. Daly T, Imbimbo BP. Metformin may reduce Alzheimer's disease risk by increasing soluble amyloid-β42 levels. *Brain*. 2025;148:e14-e15. doi:10.1093/brain/awae367

10. Chow CK, Ramasundarahettige C, Hu W, AlHabib KF, Avezum A, Cheng X, et al. Availability and affordability of essential medicines for diabetes across high-income, middle-income, and low-income countries: a prospective epidemiological study. *Lancet Diabetes Endocrinol*. 2018;6(10):798-808. doi:10.1016/S2213-8587(18)30233-X

SUPPORTING INFORMATION

Additional supporting information can be found online in the Support-
ing Information section at the end of this article.