Cited by 285Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsDiabetes Treatment and Management

The DOI matches its Crossref record; 106 of the 113 references it cites were found in a registry or an index; none of the 53 sources its claims cite is checked for support yet.

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Open access

Luchsinger, José A., Perez, Thania, Chang, Helena, Mehta, Pankaj, Steffener, Jason, Pradabhan, Gnanavalli, Ichise, Masanori, Manly, Jennifer, Devanand, Davangere P., Bagiella, Emilia·2016·Journal of Alzheimer's Disease

DOI 10.3233/jad-150493PMC PMC5079271

Open this paper in CoChat — free account

Abstract

Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (aMCI) with the goal of collecting preliminary data on feasibility, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with aMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty percent of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7±8.5 versus 5.3±8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 12-month pilot randomized placebo-controlled trial of metformin in 80 overweight/obese adults with amnestic mild cognitive impairment, metformin was feasible and safe but poorly tolerated at the maximum dose. After adjustment for baseline ADAS-cog, metformin improved Selective Reminding Test total recall versus placebo, while ADAS-cog, imaging, and plasma Aβ42 outcomes did not differ significantly.

Key findings

Metformin was not tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum 2000 mg/day. No serious adverse events related to metformin were reported; the 7.5% who did not tolerate it reported gastrointestinal symptoms.
After adjusting for baseline ADAS-cog, SRT total recall favored metformin (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02), with a metformin-vs-placebo difference in change of 4.4 ± 8.5 words. The highest metformin dose was associated with 5.3 ± 10.0 more words in SRT total recall (p = 0.03) in post hoc analysis.
ADAS-cog differences were not significant after adjustment; the posterior cingulate-precuneus rCMRgl difference favored metformin but was not significant (2.0 ± 6.3% vs. 0.0 ± 6.0%; p = 0.36). Plasma Aβ42 changes were not significant (metformin 0.69 ± 18.5 pg/ml vs. placebo −4.40 ± 23.51 pg/ml; p = 0.3).
Fasting insulin increased more in placebo than metformin (13.8 vs. 4.7 IU/ml; p = 0.09), and hsCRP decreased with metformin but increased with placebo (−0.3 vs. 1.0 mg/dl; p = 0.07).

Methods

Double-blind, placebo-controlled randomized pilot trial at a single site (Columbia University Medical Center); 80 men and women aged 55–90 years with amnestic MCI by Petersen criteria, BMI ≥25 kg/m², and without treated diabetes were randomized 1:1 to metformin 1000 mg twice daily or matching placebo for 12 months, stratified by APOE-ε4.
Co-primary clinical outcomes were 12-month changes in Selective Reminding Test total recall and ADAS-cog; secondary imaging outcome was change in posterior cingulate-precuneus relative glucose uptake on FDG PET/MRI; plasma Aβ42 was exploratory.
Analysis used ANCOVA with intent-to-treat and last-observation-carried-forward imputation, adjusting for baseline variables that differed between arms; post hoc analyses examined metformin dose and strata by age, APOE-ε4, BMI, HbA1c, and fasting insulin.

Limitations

Stated: the study was a pilot with a relatively small sample size, results may be due to chance, findings were inconsistent between SRT and ADAS-cog, post hoc analyses are subject to chance, and the study was not powered to detect imaging differences.
Stated: recruitment was challenging, requiring 32 months and screening 1426 by telephone and 331 in person; most participants could not achieve the maximum metformin dose, and some could not tolerate metformin at all.
Evident from the text: it was a single-site study; 65 of 80 participants completed 12 months, and imaging follow-up was completed in 33 of 40 invited participants, which further limits precision and generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3233/jad-150493

Cites

106 of 106 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 53 cited sources checked · 0 supported · 0 flagged

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no serious adverse events related to metformin.”
- Also stated in: § Compliance with metformin and adverse events · plain
  “In terms of safety, there were no serious adverse events related to metformin and the 7.5% of persons who were not able to tolerate metformin reported gastrointestinal symptoms.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02).”
- Also stated in: § Changes in the clinical outcomes · plain
  “after adjustment for baseline ADAS-Cog the metformin group showed significantly greater improvement in SRT total recall compared to placebo (difference in changes in total recall of the SRT of metformin vs. placebo= 4.4 ± 8.5 words)”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Changes from baseline to 12 month in the posterior cingulate-precuneus rCMRgl, adjusted for cerebellar CMRgl uptake, showed a difference favoring metformin that was not statistically significant (2.0 ± 6.3% vs. 0.0 ± 6.0%; p=0.36).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in Biomarker outcomes
Strength:plain· not yet calibratedn = 40
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Rests on an assumption: The posterior cingulate-precuneus and precuneus share the same pathological features in Alzheimer's disease.
- Rests on an assumption: A 2-week washout period is sufficient to ensure that changes in rCMRgl are not due to acute changes in glucose due to metformin.

Show all 41 claims

It may state two separate claims as one. 42
Probably not a substantial claim. 31

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose.”
- Also stated in: § Compliance with metformin and adverse events · plain
  “15% remained on 500 mg a day (1 tablet), 35% remained on 1000 mg a day (2 tablets), 32.5% remained on 1500 mg a day (3 tablets), and 10% tolerated the maximum dose of 2,000 mg a day (4 tablets).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
Strength:plain· not yet calibratedn = 80
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Thus, AMCI is considered a high risk group for dementia [6] and has become a common target for secondary prevention.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Introduction
What the sources say
- Not checked yetcites [6] Petersen, 2009, Mild cognitive impairment: Ten years later, Arch Neurol source
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
What the sources say
- Not checked yetcites [25] Luchsinger, 2004, Hyperinsulinemia and risk of Alzheimer disease, Neurology source
- Not checked yetcites [26] Peila, 2004, Fasting insulin and incident dementia in an elderly population of Japanese-American men, Neurology source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The natural history of AD starts slowly in late middle age with mild memory deficits that progress to amnestic mild cognitive impairment (AMCI) [6], which in turn progresses to dementia [7].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Introduction
What the sources say
- Not checked yetcites [6] Petersen, 2009, Mild cognitive impairment: Ten years later, Arch Neurol source
- Not checked yetcites [7] Cummings, 2004, Alzheimer’s disease, N Engl J Med source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
What the sources say
- Not checked yetcites [10] Luchsinger, 2010 source
- Not checked yetcites [11] Luchsinger, 2010, Type 2 diabetes, related conditions, in relation and dementia: An opportunity for prevention?, J Alzheimers Dis source
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“an expert panel from NIH concluded in 2010 that there was insufficient evidence to recommend treatment of AMCI or prevention for AD [9].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Introduction
What the sources say
- Not checked yetcites [9] (2010) NIH consensus development conference statement on preventing Alzheimer’s disease and cognitive decline. NIH Consensus and State-of-the-Art Statements, volume 27, number 4.
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim.
In the paper
“it has been hypothesized that pharmacologic strategies effective in preventing diabetes while decreasing insulin resistance may prevent AD [24].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Introduction
What the sources say
- Not checked yetcites [24] Ferrannini, 2014, The target of metformin in type 2 diabetes, N Engl J Med source
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✗ Asserted: fails✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. The authors may not put it forward as true.
None of the sources cited for this claim have been checked yet.
In the paper
“Genotyping of APOE polymorphisms rs7412 and rs429358 was performed at PreventionGenetics (www.preventiongenetics.com) with an array tape [58] using allele-specific PCR with universal molecular beacons [59, 60]. DNA sequencing of positive control DNA samples were completed to assure correct assignment of alleles.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Other measures
What the sources say
- Not checked yetcites [58] Tuan, 2003, Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance, Am J Cardiol source
- Not checked yetcites [59] Ridker, 2004, High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: From concept to clinical practice to clinical benefit, Am Heart J source
- Not checked yetcites [60] Ridker, 2007, Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: Implications for longevity, Nutr Rev source
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The finding that diabetes and insulin resistance are related to an increased risk of Alzheimer's dementia has prompted the exploration of related strategies for treatment and prevention of AD [11].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [11] Luchsinger, 2010, Type 2 diabetes, related conditions, in relation and dementia: An opportunity for prevention?, J Alzheimers Dis source
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Lifestyle interventions (exercise and diet) are the best insulin sensitizers, but require substantial support and resources in clinical trials that are difficult to sustain in the long term and replicate in “real world” settings [65].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [65] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Among the pharmacologic strategies, the thiazolidenidiones, also known as PPAR-gamma agonists, are powerful insulin sensitizers effective in lowering insulin resistance [66] and preventing T2D [67], with efficacy similar to lifestyle strategies and greater than metformin [68].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [66] Nathan, 2007, Trials that matter: Rosiglitazone, ramipril, and the prevention of type 2 diabetes, Ann Intern Med source
- Not checked yetcites [67] Nathan, 2007, Rosiglitazone and cardiotoxicity –weighing the evidence, N Engl J Med source
- Not checked yetcites [68] Risner, 2006, Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease, Pharmacogenomics J source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The data coordinating center at Department of Biostatistics at Columbia University Medical Center generated the random allocation sequence.”
- Also stated in: § Statistical Analyses · plain
  “Only the statistician had access to the randomization sequence. The assistant assigning the participants to interventions and the staff recruiting and evaluating participants did not have access to the randomizaion sequence.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Metformin is a safe, inexpensive medication available in generic form with proven efficacy in treating and preventing T2D though the reduction of peripheral glucose and insulin levels [25, 26].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Introduction
What the sources say
- Not checked yetcites [25] Luchsinger, 2004, Hyperinsulinemia and risk of Alzheimer disease, Neurology source
- Not checked yetcites [26] Peila, 2004, Fasting insulin and incident dementia in an elderly population of Japanese-American men, Neurology source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“In the DPP, metformin was more effective than lifestyle intervention in preventing T2D after 10 years [65].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [65] Kahn, 2006, Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy, N Engl J Med source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The thiazolidinedione rosiglitazone was tested for secondary prevention of cognitive decline in mild AD among persons without T2D and was found to be non-efficacious in a phase III trial[71] after promising results in a pilot study [72].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [71] Tian, 2004, Association between apolipoprotein E e4 allele and arteriosclerosis, cerebral amyloid angiopathy, and cerebral white matter damage in Alzheimer’s disease, J Neurol Neurosurg Psychiatry source
- Not checked yetcites [72] The Diabetes Prevention Program Research, Group, 2005, Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance, Diabetes source
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“T2D[77] in persons at risk”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [77] Watson, 2004, Modulation of memory by insulin and glucose: Neuropsychological observations in Alzheimer’s disease, Eur J Pharmacol source
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“inflammation and thrombosis[75]”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [75] Nathan, 2002, Initial management of glycemia in type 2 diabetes mellitus, N Engl J Med source
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“metformin has been reported to increase production of Aβ in a cell culture model [84]”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [84] Li, 2012, Metformin attenuates Alzheimer’s disease-like neuropathology in obese, leptin-resistant mice, Pharmacol Biochem Behav source
Strength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, they have concerning side effects including edema, congestive heart failure (CHF), and in the case of rosiglitazone, myocardial infarction (MI) [69], which led to a black box warning from the Food and Drug Administration (FDA) [70].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [69] Watson, 2005, Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: A preliminary study, Am J Geriatr Psychiatry
- Not checked yetcites [70] Dunn, 1995, A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus, Drugs source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“an epidemiologic study that showed that metformin is related to lower AD risk among persons with T2D [89].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [89] Skinner, 2012, The Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): An expansion of the ADAS-Cog to improve responsiveness in MCI, Brain Imaging Behav source
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“decreases in plasma Aβ-42 predict future AD[94].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [94] Cohen, 1988
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the risk of the metabolic syndrome[76]”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [76] Park, 2001, Cognitive effects of insulin in the central nervous system, Neurosci Biobehav Rev source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“two retrospective studies reported that among persons with T2D, a diagnosis of dementia was associated with metformin use[85, 86].”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
What the sources say
- Not checked yetcites [85] Gupta, 2011, Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes, Neuropharmacology source
- Not checked yetcites [86] Hsu, Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin, J Alzheimers Dis source
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.

64 of 64

The paper relies on this without support.
The posterior cingulate-precuneus and precuneus share the same pathological features in Alzheimer's disease.
“This ROI included the Precuneus & Posterior Cingulate gyrus together, because they share the same pathological features in AD.”
The paper relies on this without support.
Persons with an HbA1c of 6.5% or less are unlikely to receive pharmacologic treatment for type 2 diabetes, including metformin, during the 12 months of the study.
“We chose the cutoff of 6.5% in HbA1c because persons with this level of HbA1c seemed unlikely to receive pharmacologic treatment for T2D, including metformin, during the 12 months of the study.”
The paper relies on this without support.
A Telephone Interview for Cognitive Status score greater than 34 out of 41 indicates normal cognition and persons with this score are unlikely to have memory impairment.
“A TICS Score > 34 out of 41 was considered normal cognition. Persons with this score were not invited to participate.”
The paper relies on this without support.
A 2-week washout period is sufficient to ensure that changes in rCMRgl are not due to acute changes in glucose due to metformin.
“However, we conducted a washout period of 2 weeks [54] at the end of the trial before performing FDG PET to ensure that changes in rCMRgl were not due to acute changes in glucose due to metformin.”
The authors state this as an assumption.
Metformin acts on the AD process through reduction of peripheral insulin levels that affect brain clearance of Aβ.
“we postulate that it acts on the AD process through reduction of peripheral insulin levels that affect brain clearance of Aβ [79-81].”

5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Conflicting accounts of who was invited for brain imaging
Minor
The design section says half of the 80 participants were invited to the imaging sub-study, then says all participants were invited for brain imaging.

1 of 1

Statistical Power Analysis for the Behavioral Sciences
Muller, K. E., & Cohen, J. (1989) · Technometrics · doi:10.2307/1270020 · Cited by 99,603
“Mini-mental state”
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282 · cited 1×
“Mild Cognitive Impairment (CGIC-MCI) [43], the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised [44], the Mini-Mental Status Exam (MMSE) [45], the Neuropsychiatric Inventory Questionnaire [46], and the digit span backwards [47].”
Statistical power analysis for the behavioral sciences
Cohen, J. (1990) · Computers Environment and Urban Systems · doi:10.1016/0198-9715(90)90050-4 · Cited by 65,417
[Japanese version of the Neuropsychiatric Inventory--a scoring system for neuropsychiatric disturbance in dementia patients].
Hirono, N., Mori, E., Ikejiri, Y., Imamura, T., Shimomura, T., Hashimoto, M., Yamashita, H., & Ikeda, M. (1997) · PubMed · Cited by 21,012
Special Care Units and Traditional Care in Dementia: Relationship with Behavior, Cognition, Functional Status and Quality of Life - A Review
Kok, J. S., Berg, I. J., & Scherder, E. J. A. (2013) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000353441 · Cited by 20,589
Older Adults' Reasons for Using Technology while Aging in Place
Peek, S. T. M., Luijkx, K. G., Rijnaard, M. D., Nieboer, M. E., van der Voort, C. S., Aarts, S., van Hoof, J., Vrijhoef, H. J., & Wouters, E. (2015) · Gerontology · doi:10.1159/000430949 · Cited by 19,852
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa012512 · Cited by 19,011 · cited 2×
“Metformin is usually the ﬁrst step in pharmacological treatment of T2D [75], but it is increasingly used for T2D prevention based on the ﬁndings of the landmark Diabetes Prevention Program (DPP) [74], the largest trial of metformin among persons without T2D.”
Sensitivity and False Alarm Rate of a Fall Sensor in Long-Term Fall Detection in the Elderly
Kangas, M., Korpelainen, R., Vikman, I., Nyberg, L., & Jämsä, T. J. (2014) · Gerontology · doi:10.1159/000362720 · Cited by 19,007
Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: The evidence report
(1998) · PsycEXTRA Dataset · doi:10.1037/e565682010-001 · Cited by 9,453
Prevalence of Overweight and Obesity in the United States, 1999-2004
Ogden, C. L., Carroll, M. D., Curtin, L. R., McDowell, M. A., Tabak, C. J., & Flegal, K. M. (2006) · JAMA · doi:10.1001/jama.295.13.1549 · Cited by 8,720

Flagged first, then by citations

Show all 113 references

7 of the 113 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

Perez, 2011, II clinical trial of metformin in amnestic MCI: Rationale, methods, and barriers and enablers of successful recruitment, J Nutr Health Aging, 15, S14
Weschler, 1987, Wechsler Memory Scale-revised manual
Weschler, 1981, Manual for the adult Weschler intelligence scale-Revised

Sorted by citations

Items 101–200 of 282

Oxidative Stress in the Pathogenesis of Alzheimer's Disease and Cerebrovascular Disease with Therapeutic Implications
Jurcău, A., & Simion, A. (2020) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527319666200303121016 · Cited by 38
Targeting ageing and preventing organ degeneration with metformin
Sunjaya, A. P., & Sunjaya, A. F. (2020) · Diabetes & Metabolism · doi:10.1016/j.diabet.2020.09.009 · Cited by 37
Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications
Chen, J., He, H., Ye, Q., Feng, F., Wang, W., Gu, Y., Han, R., & Xie, C. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02487-7 · Cited by 37
A geroscience motivated approach to treat Alzheimer’s disease: Senolytics move to clinical trials
Gonzales, M. M., Krishnamurthy, S., Garbarino, V. R., Daeihagh, A. S., Gillispie, G. J., Deep, G., Craft, S., & Orr, M. E. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111589 · Cited by 37
Comparative effect of metformin versus sulfonylureas with dementia and Parkinson’s disease risk in US patients over 50 with type 2 diabetes mellitus
Newby, D., Linden, A. B., Fernandes, M., Winchester, L. M., Molero, Y., Sproviero, W., Ghose, U., Li, Q. S., Launer, L. J., van Duijn, C. M., et al. (2022) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2022-003036 · Cited by 35
Repurposing and clinical attributes of antidiabetic drugs for the treatment of neurodegenerative disorders
Birajdar, S. V., Mazahir, F., Alam, M. I., Kumar, A., & Yadav, A. K. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176117 · Cited by 37
High-Fat Diets in Animal Models of Alzheimer’s Disease: How Can Eating Too Much Fat Increase Alzheimer’s Disease Risk?
Valentin‐Escalera, J., Leclerc, M., & Calon, F. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230118 · Cited by 37
Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases
Liu, J., Ting, J. P., Al-Azzam, S., Ding, Y., & Afshar, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062805 · Cited by 37
Dementia risk in patients with type 2 diabetes: comparing metformin with no pharmacological treatment
Zheng, B., Su, B., Ahmadi‐Abhari, S., Kapogiannis, D., Tzoulaki, I., Riboli, E., & Middleton, L. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13349 · Cited by 34
“No 2).”
Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders
Isop, L. M., Neculau, A. E., Necula, R. D., Kakucs, C., Moga, M., & Dima, L. (2023) · Pharmaceuticals · doi:10.3390/ph16121714 · Cited by 36
Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases
Plascencia‐Villa, G., & Perry, G. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512486 · Cited by 33
“A pilot randomized clinical trial of metformin (1000 mg twice a day for 12 months) in elderly subjects with MCI indicated that the treatment was tolerated but had no significant effects on cognitive measures (ADAS-cog score), CSF biomarkers, or cerebral glucose metabolism (PET scans) [18].”
Background
Repurposing antidiabetic drugs for Alzheimer's disease: A review of preclinical and clinical evidence and overcoming challenges
Tran, J., Parekh, S., Rockcole, J., Wilson, D., & Parmar, M. S. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.123001 · Cited by 35
Review of Advanced Drug Trials Focusing on the Reduction of Brain Beta-Amyloid to Prevent and Treat Dementia
Decourt, B., Noorda, K., Noorda, K. J., Shi, J., & Sabbagh, M. N. (2022) · Journal of Experimental Pharmacology · doi:10.2147/jep.s265626 · Cited by 33
“Overall, the group treated with the drug performed significantly better on the SRT scale.(58) However, some toxic events limited the maximum dose tolerated by study subjects, which prompted the design of an improved multisite Phase II/III study for the use of metformin to prevent AD (NCT04098666).”
Background
Mechanisms of ageing: growth hormone, dietary restriction, and metformin
Khan, J., Pernicova, I., Nisar, K., & Korbonits, M. (2023) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(23)00001-3 · Cited by 34
Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials
Mantik, K. E. K., Kim, S., Gu, B., Moon, S., Kwak, H., Park, D., & Kang, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411450 · Cited by 36
Targeting Insulin for Alzheimer’s Disease: Mechanisms, Status and Potential Directions
Lee, J. H., Jahrling, J. B., Denner, L. A., & Dineley, K. T. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179923 · Cited by 36
Metformin in the Prevention of Alzheimer's Disease and Alzheimer's Disease Related Dementias
Tahmi, M., & Luchsinger, J. A. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.113 · Cited by 32
“…amnestic mild cognitive impairment without T2D (n= 80, mean age= 65 years), randomization to 1000 mg of metformin twice daily was safe and feasible and resulted in better performance in memory, measured by the total recall in the Buschke selective reminding test compared to the placebo group (105).”
MethodSelf-citation
Autophagy in ageing and ageing-related neurodegenerative diseases
Karabiyik, C., Frake, R. A., Park, S. J., Tanasa, M. P., & Rubinsztein, D. C. (2021) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2021.05 · Cited by 31
Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation
Arbo, B. D., Schimith, L. E., dos Santos, M. G., & Hort, M. A. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174800 · Cited by 33
Antidiabetic therapies and Alzheimer disease.
Bendlin, B. B. (2019) · PubMed Central · Cited by 30
Crosstalk between Alzheimer’s disease and diabetes: a focus on anti-diabetic drugs
Goodarzi, G., Tehrani, S. S., Fana, S. E., Moradi‐Sardareh, H., Panahi, G., Maniati, M., & Meshkani, R. (2023) · Metabolic Brain Disease · doi:10.1007/s11011-023-01225-3 · Cited by 29
“Although promising results were obtained for the memory, no differences were observed for ADAS-Cog12, CSF, Aβ42, and cerebral glucose metabolism (Luchsinger et al. 2016).”
Result
Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer’s Disease and Depression
El Massry, M., Alaeddine, L. M., Ali, L., Saad, C., & Eid, A. A. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867327666200908114902 · Cited by 27
Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer’s Disease
Alfei, S., & Zuccari, G. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020844 · Cited by 28
Neurovascular Coupling in Type 2 Diabetes With Cognitive Decline. A Narrative Review of Neuroimaging Findings and Their Pathophysiological Implications
Barloese, M. C. J., Bauer, C., Petersen, E. T., Hansen, C. S., Madsbad, S., & Siebner, H. R. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.874007 · Cited by 34
Impaired autophagy in amyloid-beta pathology: A traditional review of recent Alzheimer's research
Yuan, M., Wang, Y., Huang, Z., Jing, F., Qiao, P., Zou, Q., Li, J., & Cai, Z. (2022) · Journal of Biomedical Research · doi:10.7555/jbr.36.20220145 · Cited by 26
Pharmacological Approaches Using Diabetic Drugs Repurposed for Alzheimer’s Disease
Adem, M. A., Decourt, B., & Sabbagh, M. N. (2024) · Biomedicines · doi:10.3390/biomedicines12010099 · Cited by 30
“The study had two primary clinical outcomes: changes in the total recall of the selective reminding test (SRT) from baseline to 12 months and the score of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) [53].”
BackgroundMethodInfluential
A new clinical age of aging research
Zhang, Z., Yang, R., Zi, Z., & Liu, B. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.08.004 · Cited by 25
A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism
Fernandez, A. M., Hernández-Garzón, E., Guerrero‐Gómez, D., Miranda‐Vizuete, A., & Torres‐Alemán, I. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.08.034 · Cited by 24
Metformin and cyanidin 3- O -galactoside from Aronia melanocarpa synergistically alleviate cognitive impairment in SAMP8 mice
Wen, H., Tian, H., Liu, C., Zhang, X., Peng, Y., Yang, X., Chen, F., & Li, J. (2021) · Food & Function · doi:10.1039/d1fo02122b · Cited by 25
Acute Administration of Metformin Protects Against Neuronal Apoptosis Induced by Cerebral Ischemia-Reperfusion Injury via Regulation of the AMPK/CREB/BDNF Pathway
Liu, K., Li, L., Liu, Z., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.832611 · Cited by 24
The use of geroprotectors to prevent multimorbidity: Opportunities and challenges
Morsli, S., & Bellantuono, I. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111391 · Cited by 24
Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer’s disease and cardiovascular diseases
Waigi, E. W., Webb, R. C., Moss, M. A., Uline, M. J., McCarthy, C. G., & Wenceslau, C. F. (2023) · GeroScience · doi:10.1007/s11357-023-00748-y · Cited by 26
Salidroside prevents diabetes‑induced cognitive impairment via regulating the Rho pathway
Hao, X., Yuan, J., & Dong, H. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9621 · Cited by 23
“As one of the rare medicinal herbs, the whole plant of Rhodiola can be used as a medicine with notable antihypoxic, cold-relieving, antifatigue and antiviral effects, in addition to delaying aging and preventing geriatric disease (15).”
Background
Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today?
de la Monte, S. M. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240069 · Cited by 28
Exploring the mechanism of metformin action in Alzheimer’s disease and type 2 diabetes based on network pharmacology, molecular docking, and molecular dynamic simulation
Shi, X., Li, L., Liu, Z., Wang, F., & Huang, H. (2023) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188231187493 · Cited by 24
“27,28 In experimental studies of non-diabetic animals, a meta-analysis 29 and clinical research 13,30 confirmed that metformin benefits the cognition of animals with AD.”
Background
Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials
Zarini-Gakiye, E., Amini, J., Sanadgol, N., Vaezi, G., & Kazem, P. (2020) · Current Molecular Pharmacology · doi:10.2174/1874467213666200422090135 · Cited by 22
Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer’s disease
Abdulhameed, N., Babin, A., Hansen, K. M., Weaver, R. R., Banks, W. A., Talbot, K., & Rhea, E. M. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01537-1 · Cited by 25
Targeting the liver in dementia and cognitive impairment: Dietary macronutrients and diabetic therapeutics
Hunt, N. J., Wahl, D., Westwood, L. J., Lockwood, G. P., Couteur, D. G. L., & Cogger, V. C. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114537 · Cited by 21
“In an RCT of non-diabetics with MCI given metformin for 8 weeks or 12 months, slight improvements in AD Assessment Scale-Cognitive Subscale test scores, cerebral spinal fluid Aβ42 and cerebral glucose metabolism were observed [178,179].”
Background
Metformin Attenuates Tau Pathology in Tau-Seeded PS19 Mice
Zhao, S., Fan, Z., Zhang, X., Li, Z., Shen, T., Li, K., Yan, Y., Yuan, Y., Pu, J., Tian, J., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01316-6 · Cited by 22
“Metformin administration for 12 months is associated with better performance in selective reminding tests in overweight patients aged 55 to 90 with amnestic mild cognitive impairment [33].”
Background
Therapies for Alzheimer’s disease: a metabolic perspective
Domingues, R., Pereira, C., Cruz, M. T., & Silva, A. (2021) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2021.01.011 · Cited by 21
Emerging uncertainty on the anti-aging potential of metformin
Keys, M. T., Hallas, J., Miller, R. A., Suissa, S., & Christensen, K. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102817 · Cited by 24
“However, pilot clinical trials have reported inconsistent but some positive evidence across a range of exploratory outcomes in various age-related cognitive syndromes (Hartman et al., 2019; Am et al., 2017; Lin et al., 2018; Luchsinger et al., 2016).”
Metformin, Cognitive Decline, And Brain Pathology
Sood, A., Capuano, A. W., Wilson, R. S., Barnes, L. L., Kapasi, A., Bennett, D. A., & Arvanitakis, Z. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.10.005 · Cited by 21
Insights into the Role of Histone Methylation in Brain Aging and Potential Therapeutic Interventions
Vitorakis, N., & Piperi, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417339 · Cited by 24
“Currently, only metformin administration has been shown to improve cognitive impairment in a pilot randomized placebo-controlled clinical trial [96].”
Background
Glycation in Alzheimer’s Disease and Type 2 Diabetes: The Prospect of Dual Drug Approaches for Therapeutic Interventions
Ayoub, S., Arabi, M., Al-Najjar, Y. A., Laswi, I., Outeiro, T. F., & Châari, A. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05051-9 · Cited by 23
“A pilot 12-month RCT of metformin (1000 mg BID) in 80 overweight adults with amnestic MCI found memory improvement on one test (SRT total recall) favoring metformin (9.7 vs. 5.3 point gain, p = 0.02) [194], though other measures were unchanged.”
Influential
Clusterin as a Potential Biomarker of Obesity-Related Alzheimer’s Disease Risk
Bradley, D. P. (2020) · Biomarker Insights · doi:10.1177/1177271920964108 · Cited by 20
Baseline Neurocognitive Impairment (NCI) Is Associated With Incident Frailty but Baseline Frailty Does Not Predict Incident NCI in Older Persons With Human Immunodeficiency Virus (HIV)
Masters, M. C., Perez, J., Wu, K., Ellis, R. J., Goodkin, K., Koletar, S. L., Andrade, A. S., Yang, J., Brown, T. T., Palella, F. J., et al. (2021) · Clinical Infectious Diseases · doi:10.1093/cid/ciab122 · Cited by 22
Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention
Soldevila‐Domenech, N., Cuenca‐Royo, A., Babió, N., Forcano, L., Nishi, S. K., Vintró‐Alcaraz, C., Gómez-Martínez, C., Jiménez‐Múrcia, S., Fernández-Carrión, R., Gomis‐González, M., et al. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.742586 · Cited by 19
Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors
Dahhan, N. Z. A., Cox, E., Nieman, B. J., & Mabbott, D. (2022) · Neuron · doi:10.1016/j.neuron.2022.04.009 · Cited by 23
Alzheimer's Disease and Frontotemporal Dementia: A Review of Pathophysiology and Therapeutic Approaches
Kelliny, S., Zhou, X., & Bobrovskaya, L. (2025) · Journal of Neuroscience Research · doi:10.1002/jnr.70046 · Cited by 27
“Studies showed that treatment with metformin in non-diabetic obese patients with MCI improved some aspects of cognition (Luchsinger et al. 2016; Weinberg et al. 2024; Rosell-Díaz and Fernández-Real 2023).”
Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications
Chen, Z., Mao, Z., Tang, W., Shi, Y., Liu, J., & You, Y. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00517-1 · Cited by 27
“In patients with MCI, metformin has been shown to enhance blood perfusion in the orbitofrontal cortex and ameliorate cognitive impairment [392–394], while its effects in AD patients remain underexplored.”
The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties
Ogura, J., & Yamaguchi, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126542 · Cited by 19
“Moreover, while a few randomized controlled trials have been conducted [90,91], the effect of metformin on cognitive function remains controversial.”
Background
Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease
Woodfield, A., Gonzales, T., Helmerhorst, E., Laws, S. M., Newsholme, P., Porter, T., & Verdile, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415811 · Cited by 19
“The other trial in those with nondementia vascular cognitive impairment reported an improvement in their ADAS-Cog scores, executive functioning and verbal learning [86].”
Background
Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases
Dai, J., Ports, K. D., Corrada, M. M., Odegaard, A., O’Connell, J., & Jiang, L. (2022) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220002 · Cited by 17
Modulation of Mitochondrial Function as a Therapeutic Strategy for Neurodegenerative Diseases
Trushina, E. V., Nguyen, T. K. O., & Trushin, S. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.108 · Cited by 17
Effect of Metformin on Plasma and Cerebrospinal Fluid Biomarkers in Non-Diabetic Older Adults with Mild Cognitive Impairment Related to Alzheimer’s Disease
Weinberg, M. S., He, Y., Kivisäkk, P., Arnold, S. E., & Das, S. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230899 · Cited by 20
“Luchsinger et al. [16], in a study of 80 over-weight individuals with amnestic MCI, found that twelve months of metformin treatment signiﬁcantly improved total recall of the Selective Reminding Test, without improving scores on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog).”
Glucose-lowering drugs, cognition, and dementia: The clinical evidence
Wu, C., Shapiro, L. R., Ouk, M., MacIntosh, B. J., Black, S. E., Shah, B. R., & Swardfager, W. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104654 · Cited by 20
Protocol for a Randomized Phase II/III Double-Blind Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Extended-Release Metformin in Amnestic Mild Cognitive Impairment
Luchsinger, J. A., Devanand, D. P., Goldberg, T. E., Cammack, S., Hernández-Santiago, G., Oishi, K., Jagust, W., Baker, S. L., Landau, S. M., Yenokyan, G., et al. (2025) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000677 · Cited by 20
Self-citation
RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus
O'Brien, J. T., Chouliaras, L., Sultana, J., Taylor, J., Ballard, C. G., on behalf of the RENEWAL Study Group, Aarsland, D., Blanc, F., Boeve, B. F., Brooks, D. J., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01103-7 · Cited by 17
“In another study, 80 overweight participants with amnestic MCI were randomised to receive metformin or placebo for 12 months [150].”
Method
Amyloid-beta metabolism in age-related neurocardiovascular diseases
Aivalioti, E., Georgiopoulos, G. A., Tual‐Chalot, S., Bampatsias, D., Delialis, D., Sopova, K., Drakos, S. G., Stellos, K., & Stamatelopoulos, K. S. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae655 · Cited by 20
Effects of commonly prescribed drugs on cognition and mild cognitive impairment in healthy elderly people
del Ser, T., Zea‐Sevilla, M. A., Valentí, M., Olazarán, J., López‐Álvarez, J., Rebollo-Vázquez, A., Ávila‐Villanueva, M., Frades, B., Medina, M., & Fernández‐Blázquez, M. A. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881119857206 · Cited by 16
Dietary administration of D-chiro-inositol attenuates sex-specific metabolic imbalances in the 5xFAD mouse model of Alzheimer’s disease
López-Gambero, A. J., Pacheco-Sánchez, B., Rosell‐Valle, C., Vera, D. M., Navarro, J. A., Fernández‐Arjona, M. D. M., de Ceglia, M., Sanjuan, C., Simon, V., Cota, D., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112994 · Cited by 16
Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research
Diniz, B. S., Seitz‐Holland, J., Sehgal, R., Kasamoto, J., Higgins‐Chen, A., & Lenze, E. J. (2023) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2023.09.014 · Cited by 15
The Association between Metformin Use and Risk of Developing Severe Dementia among AD Patients with Type 2 Diabetes
Xue, Y., & Xie, X. (2023) · Biomedicines · doi:10.3390/biomedicines11112935 · Cited by 15
“A double-blind placebo-controlled randomized pilot trial [28] also found that there was no signiﬁcant relationship between metformin and memory change in patients with mild cognitive impairment.”
Background
The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline
Bang, E., Lee, B., Park, J.-O., Jang, Y., Kim, A., Kim, S., & Shin, H. (2018) · Experimental Neurobiology · doi:10.5607/en.2018.27.1.45 · Cited by 15
“Several studies have provided evidence that metformin can slow or improve cognitive function decline [22]; however, whether metabolic control by metformin contributes to its beneficial effects on cognitive function remains unclear.”
Background
Could metformin be therapeutically useful in Huntington’s disease?
Tang, B. L. (2019) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0072 · Cited by 15
Delineating the Role of Mitophagy Inducers for Alzheimer Disease Patients
Wang, W., Han, R., He, H., Wang, Z., Luan, X., Li, J., Feng, L., Chen, S., Aman, Y., & Xie, C. (2021) · Aging and Disease · doi:10.14336/ad.2020.0913 · Cited by 15
“Finally, we identified 11 eligible clinical trial of mitophagy inducers for AD patients [50-61] (Figure 3).”
Background
Exploring Autophagy Inducing Molecules: Targeting Diverse Pathways in Alzheimer's Disease Management
Singh, B., Mahajan, S., Abdella, S., Khan, R., & Garg, S. (2025) · Medicinal Research Reviews · doi:10.1002/med.70013 · Cited by 16
Disrupting the Mood and Obesity Cycle: The Potential Role of Metformin
Doan, S. N., Patel, S. K., Xie, B., Nelson, R. A., & Yee, L. D. (2023) · Obesities · doi:10.3390/obesities3010006 · Cited by 14
“Notably, a randomized, placebo-controlled trial of metformin in adults (55–90 years old, n = 80) with amnestic mild cognitive impairment and without treated diabetes showed that metformin significantly improved cognitive performance [142].”
Background
Association of Metformin and Other Diabetes Medication Use and the Development of New-Onset Dry Age-Related Macular Degeneration: A Case–Control Study
Kaufmann, G. T., Hyman, M. J., Gonnah, R., Hariprasad, S. M., & Skondra, D. (2023) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.64.11.22 · Cited by 14
Targeting immunometabolic pathways for combination therapy in Alzheimer's disease
Erichsen, J. M., & Craft, S. (2023) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12423 · Cited by 13
“48 No treatment-related differences were observed for the ADAS-Cog, CSF A β 42, or cerebral glucose metabolism assessed with FDG-PET.”
Method
Dementia risk reduction: why haven't the pharmacological risk reduction trials worked? An in‐depth exploration of seven established risk factors
Peters, R. K., Breitner, J. C. S., James, S., Jicha, G. A., Meyer, P., Richards, M., Smith, A. D., Yassine, H. N., Abner, E. L., Hainsworth, A. H., et al. (2021) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12202 · Cited by 19
A high throughput drug screening paradigm using transgenic Caenorhabditis elegans model of Alzheimer’s disease
Teo, E., Lim, J., Fong, S., Larbi, A., Wright, G. D., Tolwinski, N. S., & Gruber, J. (2019) · Translational Medicine of Aging · doi:10.1016/j.tma.2019.12.002 · Cited by 18
Alzheimer’s disease and type 2 diabetes mellitus: similarities in pathomechanisms lead to therapeutic opportunities
Bednarz, K., & Siuda, J. S. (2021) · Neurologia i Neurochirurgia Polska · doi:10.5603/pjnns.a2021.0056 · Cited by 15
“An improvement in the ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive subscale) score, which measures cognitive abilities, was also observed in patients with MCI who were overweight or obese, but not diabetic [69].”
Effect of antidiabetic drugs in Alzheimer´s disease: a systematic review of preclinical and clinical studies
Corraliza-Gómez, M., Vargas-Soria, M., & Garcı́a-Alloza, M. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00894-1 · Cited by 14
Nutritional intervention for diabetes mellitus with Alzheimer's disease
Li, Z., Li, S., Xiao, Y., Zhong, T., Yu, X., & Wang, L. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1046726 · Cited by 12
Metformin mitigates dementia risk among individuals with type 2 diabetes
Aderinto, N., Olatunji, G. D., Kokori, E., Fawehinmi, P., Moradeyo, A. A., Igwe, S. C., Ojabo, R. E., Alabi, B. O., Okafor, E. C., Ologbe, D., et al. (2024) · Clinical Diabetes and Endocrinology · doi:10.1186/s40842-024-00168-7 · Cited by 16
How close is autophagy-targeting therapy for Alzheimer's disease to clinical use? A summary of autophagy modulators in clinical studies
Fernandes, S. M., Mayer, J., Nilsson, P., & Shimozawa, M. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1520949 · Cited by 17
AMPK activators for the prevention and treatment of neurodegenerative diseases
Neumann, N. R., Thompson, D. C., & Vasiliou, V. (2021) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1991308 · Cited by 13
Intranasal delivery of metformin using metal–organic framework (MOF)-74-Mg nanocarriers
Yuan, M., Han, Z., Somayaji, Y., Nguyen, N., Hu, H., Madhu, L. N., Attaluri, S., Kodali, M., Yang, Y., Hsu, Y., et al. (2025) · Advanced Composites and Hybrid Materials · doi:10.1007/s42114-025-01227-y · Cited by 14
Effects of the SGLT2 inhibitor dapagliflozin in early Alzheimer's disease: A randomized controlled trial
Burns, J. M., Morris, J. K., Vidoni, E. D., Wilkins, H., Choi, I., Lee, P., Hunt, S. L., Mahnken, J. D., Brooks, W. M., Lepping, R. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70416 · Cited by 17
Alzheimer's disease approaches - Focusing on pathology, biomarkers and clinical trial candidates
Hroudová, J., & Fišar, Z. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111069 · Cited by 13
Diverse Applications of the Anti-Diabetic Drug Metformin in Treating Human Disease
Roberts, C.-T., Raabe, N., Wiegand, L., Shahib, A. K., & Rastegar, M. (2024) · Pharmaceuticals · doi:10.3390/ph17121601 · Cited by 13
Mechanistic and Etiological Similarities in Diabetes Mellitus and Alzheimer’s Disease: Antidiabetic Drugs as Optimistic Therapeutics in Alzheimer’s Disease
Das, S., Ramachandran, A. K., Halder, D., Akbar, S., Ahmed, B., & Joseph, A. (2022) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527321666220629162229 · Cited by 13
From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin
Campagnoli, L. I. M., Varesi, A., Fahmideh, F., Hakimizad, R., Petkovic, P., Barbieri, A., Marchesi, N., & Pascale, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199748 · Cited by 15
“Indeed, while safe and tolerated, metformin was not associated with any improvement of AD or protection against dementia risk when adjusted for biases [72,73,103,115,126,127].”
Immunometabolism Reframes Alzheimer’s Disease: From Systemic Dysmetabolism to Glial Rewiring
Bach, D., & Nguyen, L. L. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01691-0 · Cited by 15
“Its low cost, safety, and penetrance make metformin a strategic component of combination trials targeting metabolic and neuroinflammatory nodes (Luchsinger et al. 2016; Rosell-Díaz and Fernández-Real 2023 ).”
Insulin, Brain, Alzheimer’s Disease: New Evidence
Bulgakova, S. V., Иванович, Р. П., & Treneva, E. V. (2020) · Bulletin of Science and Practice · doi:10.33619/2414-2948/52/10 · Cited by 12
Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins
Gonçalves, C., Sesterheim, P., Wartchow, K. M., Bobermin, L. D., Leipnitz, G., & Quincozes‐Santos, A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.905218 · Cited by 11
New insights toward molecular and nanotechnological approaches to antidiabetic agents for Alzheimer’s disease
Pradhan, S. P., Sahu, P. K., & Behera, A. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04696-1 · Cited by 14
“Metformin, a biguanide derivative, significantly prevents amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation by blocking tumor necrosis factor-α production and enhancing amyloid-β clearance and neurogenesis [124–128].”
Background
The Potential of a Stratified Approach to Drug Repurposing in Alzheimer’s Disease
Anderson, C., Bucholc, M., McClean, P. L., & Zhang, S. (2023) · Biomolecules · doi:10.3390/biom14010011 · Cited by 13
“However, results from clinical trials are mixed, with some studies showing that metformin reduces cognitive decline [238,239], while others have found that it could worsen cognitive health [240–242].”
Result
Facilitation of hippocampal long-term potentiation and reactivation of latent HIV-1 via AMPK activation: Common mechanism of action linking learning, memory, and the potential eradication of HIV-1
Finley, J. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.04.018 · Cited by 13
“again indicating that cognitive impairment and neurodegenerative disorders characterized by memory loss may be alleviated via AMPK activation [165].”
Metformin as a Potential Prevention Strategy for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias
Tahmi, M., Benitez, R., & Luchsinger, J. A. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240495 · Cited by 11
“…in subjects with amnestic MCI without T2D ( n = 80, mean age = 65 years), randomization to 1000 mg of metformin twice daily was safe and feasible and resulted in better performance in memory, measured by the total recall in the Buschke selective reminding test compared to the placebo group [75].”
Self-citation
The Possible Role of Metformin and Fibroblast Growth Factor‐21 in Multiple Sclerosis Neuropathology: Birds of a Feather Flock Together
Abulaban, A. A., Al-Kuraishy, H. M., Al-Gareeb, A. I., Ahmed, E., Alruwaili, M., Alexiou, A. T., Papadakis, M., & Batiha, G. E. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70067 · Cited by 11
“Compared with other diabetic treatments, metformin has been reported to enhance working memory and executive brain functions in T2DM patients (Luchsinger et al. 2016; Imfeld et al. 2012).”
Retinal Microperimetry: A Useful Tool for Detecting Insulin Resistance-Related Cognitive Impairment in Morbid Obesity
Ciudin, A., Ortiz-Zúñiga, Á., Fidilio, E., Romero, D., Sánchez, M., Comas, M., González, Ó., Vilallonga, R., Simó‐Servat, O., Hernández, C., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122181 · Cited by 10
“[39] showed a slight arrest in cognitive decline related to lowered fasting insulin levels in middle-aged (65 years) non-diabetic patients with obesity (BMI 31 kg/m2) after 12 months of treatment with metformin.”
Background
Evidence for pathophysiological commonalities between metabolic and neurodegenerative diseases
Hölscher, C. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.01.007 · Cited by 10
A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro
Querfurth, H., Marshall, J., Parang, K., Rioult-Pedotti, M. S., Tiwari, R., Kwon, B., Reisinger, S., & Lee, H.-K. (2022) · PLOS ONE · doi:10.1371/journal.pone.0261696 · Cited by 9
“Promising results from early clinical trials in MCI and mild AD of insulin sensitizers (metformin, [82]), GLP-1 receptor agonist/ incretin analogs (liraglutide, [83]), intranasal (IN) insulin [84, 85] and insulin- sensitizing PPAR-γ agonists that target genes such as IRS-1, GLUT-4 and PI3K [86, 87] (Rosiglitazone, [88…”
Background
Exploitation of Autophagy Inducers in the Management of Dementia: A Systematic Review
Corasaniti, M. T., Bagetta, G., Nicotera, P., Maione, S., Tonin, P., Guida, F., & Scuteri, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021264 · Cited by 10
Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia
Behl, T., Arora, A., Sehgal, A., Singh, S., Sharma, N., Bhatia, S., Al‐Harrasi, A., BUNGAU, S. G., & Mostafavi, E. (2021) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527320666211110115257 · Cited by 9
Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity
Daniali, M., Baeeri, M., Farhadi, R., Gholami, M., Hassani, S., Nigjeh, M. N., Rahimifard, M., & Abdollahi, M. R. (2022) · Toxics · doi:10.3390/toxics10040197 · Cited by 9
Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid betaPreprint
Teo, E., Ravi, S., Barardo, D., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/708537 · Cited by 9
A multi-target therapeutic framework for Alzheimer’s disease: an integrative mechanistic review
Bajinka, O., Jallow, L., & Ozdemir, G. (2026) · Neuroscience · doi:10.1016/j.neuroscience.2026.01.010 · Cited by 10

Authors: Luchsinger, J. A., Perez, T., Chang, H., Mehta, P., Steffener, J., Pradabhan, G., Ichise, M., Manly, J., Devanand, D. P., & Bagiella, E.
Affiliations: Department of Medicine, Columbia University Medical Center, New York, NY, USA
Columbia University Irving Medical Center (US)
Mount Sinai Hospital (US)
New York Institute for Basic Research, Staten Island, NY, USA
Columbia University (US)
New York State Psychiatric Institute (US)
ORCID: Chang, Helena
Mehta, Pankaj
Steffener, Jason
Ichise, Masanori
Manly, Jennifer
Devanand, Davangere P.
Bagiella, Emilia
Venue: Journal of Alzheimer's Disease
Publisher: SAGE Publications
Published: 2016-03-15
Volume: 51
Issue: 2
Pages: 501-514
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-150493
PMC: PMC5079271
OpenAlex: W2315843281
Semantic Scholar: 051353655bd022160343f181e1c8e5bd3de5377e
Cited by: 285
References: 113
Citations by year: 2026: 22 · 2025: 33 · 2024: 29 · 2023: 40 · 2022: 42 · 2021: 32 · 2020: 29 · 2019: 20 · 2018: 24 · 2017: 11 · 2016: 3
FWCI: 17.17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Alzheimer's Drug Discovery Foundation
National Institutes of Health (UL1TR000040)
National Institute on Aging (R01AG026413)
National Center for Research Resources (UL1RR024156)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: metformin, amnestic mild cognitive impairment
MeSH terms: Aged, Aged, 80 and over, Brain, Double-Blind Method, Female, Follow-Up Studies, Glucose, Humans, Male, Metformin, Middle Aged, Peptide Fragments, Pilot Projects, Psychological Tests, Severity of Illness Index, Amyloid beta-Peptides, Treatment Outcome, Nootropic Agents, Positron-Emission Tomography, Overweight, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Abstract

Overview

AI snapshot

TL;DR

Key findings

Methods

Limitations

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks