ArticleProceedings of the National Academy of Sciences of the United States of America2009
Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06072963 (Combination of Intranasal Insulin With Oral Semaglutide to Improve Cognition and Cerebral Blood Flow), which is not on this map. Cited by 207 papers, 5 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Combination of Intranasal Insulin With Oral Semaglutide to Improve Cognition and Cerebral Blood Flow: a Feasibility Study
Who cites it
207 citing papers in PubMed, 5 syntheses or guidelines pooled it, 382 citations in OpenAlex.
- Metformin and Cognitive Performance in Patients With Type 2 Diabetes: An Umbrella Review.Neuropsychopharmacology reports · 2025Pooled it
- Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis.Frontiers in neuroscience · 2022Pooled it
- Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis.BMJ open diabetes research & care · 2020 · on this mapPooled it
- Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis.Journal of Alzheimer's disease : JAD · 2018 · on this mapPooled it
- Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2010Pooled it
- Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight Associated with Atypical Antipsychotic Use.Journal of child and adolescent psychopharmacology · 2018Trial
- Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial.Journal of Alzheimer's disease : JAD · 2016Trial
- FOXO transcription factors in Alzheimer's Disease: balancing neuroprotection and neuronal degeneration.Molecular biology reports · 2026Review
- Metformin improves RAN protein pathology, alternative splicing, and behavioral phenotypes in SCA8 mice.Life science alliance · 2026Article
- Article
- ALDOC modulates astrocytic glycolysis and AMPK/mTOR/HIF-1α signaling in Alzheimer's disease.Frontiers in neuroscience · 2026Article
- Multiple Mechanisms and Therapeutic Strategies for the Involvement of AMPK in the Development of Alzheimer's Disease.Molecular neurobiology · 2025Review
- Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.Neurotoxicity research · 2025Article
- Restoring amyloid-β42 and γ-secretase function in Alzheimer's disease.Brain : a journal of neurology · 2025Review
- Activation of the AMPK Signaling and Brain Function: A Friend or Foe?Journal of neurochemistry · 2025Review
- Metformin Improves Spatial Memory and Reduces Seizure Severity in a Rat Model of Epilepsy and Alzheimer's Disease comorbidity via PI3K/Akt Signaling Pathway.Molecular neurobiology · 2025Article
- Neuroprotective Effects of Metformin Through the Modulation of Neuroinflammation and Oxidative Stress.Cells · 2025Review
- Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease.The journal of prevention of Alzheimer's disease · 2025Article
- The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease and future strategies for targeted therapy.European journal of medical research · 2025Review
- Risk Factors, Pathological Changes, and Potential Treatment of Diabetes-Associated Cognitive Dysfunction.Journal of diabetes · 2025Review
147 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
Abstract
Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of beta-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of beta-amyloid (Abeta) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage(R)), affects APP metabolism and Abeta generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Abeta species. Furthermore, the effect of metformin on Abeta generation is mediated by transcriptional up-regulation of beta-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Abeta degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Abeta. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Abeta generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Abeta generation, in combined use, metformin enhances insulin's effect in reducing Abeta levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.