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

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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

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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

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“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.”
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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
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Sorted by citations

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums
Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., et al. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.185 · Cited by 1,597
Metformin as a tool to target aging
Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.011 · Cited by 1,096
“In an unpublished trial, non-diabetic subjects (n = 80) with mild cognitive impairment showed significant improvements in some cognitive domains after 12 months of metformin treatment (Luchsinger et al., 2016).”
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Cunnane, S. C., Trushina, E., Morland, C., Prigione, A., Casadesus, G., Andrews, Z. B., Beal, M. F., Bergersen, L. H., Brinton, R. D., de la Monte, S., et al. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0072-x · Cited by 1,003
Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches
Kellar, D., & Craft, S. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30231-3 · Cited by 832
Diabetes mellitus and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 144 prospective studies
Xue, M., Xu, W., Ou, Y.-N., Cao, X.-P., Tan, M.-S., Tan, L., & Yu, J.-T. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100944 · Cited by 715
Diabetic vascular diseases: molecular mechanisms and therapeutic strategies
Li, Y., Liu, Y., Liu, S., Gao, M., Wang, W., Chen, K., Huang, L., & Liu, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01400-z · Cited by 799
Epigenetic regulation of aging: implications for interventions of aging and diseases
Kang, W., Liu, H., Hu, Q., Wang, L., Liu, J., Zheng, Z., Zhang, W., Ren, J., Zhu, F., & Liu, G. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01211-8 · Cited by 732
Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis
Santos, C. Y., Snyder, P. J., Wu, W., Zhang, M., Echeverria, A., & Alber, J. (2017) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.01.005 · Cited by 431
The Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog): Modifications and Responsiveness in Pre-Dementia Populations. A Narrative Review
Kueper, J. K., Speechley, M. R., & Montero‐Odasso, M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170991 · Cited by 461
Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier
Tryphena, K. P., Shukla, R., Khatri, D. K., & Vora, L. K. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102481 · Cited by 438
A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup
Justice, J. N., Ferrucci, L., Newman, A. B., Aroda, V. R., Bahnson, J. L., Divers, J., Espeland, M. A., Marcovina, S., Pollak, M. N., Kritchevsky, S. B., et al. (2018) · GeroScience · doi:10.1007/s11357-018-0042-y · Cited by 359
Insulin Resistance and Neurodegeneration: Progress towards the Development of New Therapeutics for Alzheimer's Disease
de la Monte, S. M. (2017) · Drugs · doi:10.1007/s40265-016-0674-0 · Cited by 331
“In a later independent study, metformin treatment of overweight or obese, previously untreated diabetics with amnestic mild cognitive impairment had a statistical trend for positive performance effects on the selective reminding test [239].”
Background
Metformin: a review of its potential indications
Wang, Y., He, S., Feng, X., Cheng, J. Q., Luo, Y.-T., Tian, L., & Huang, Q. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s141675 · Cited by 330
“Similarly, significant improvements can be found in subjects without treated diabetes with mild cognitive impairment after 12 months of metformin treatment (1,000 mg twice a day, Table 1).(86) In addition, Cheng et al reported that T2DM patients with metformin have lower risk of dementia than those with other diabetes…”
The Therapeutic Potential of Metformin in Neurodegenerative Diseases
Rotermund, C., Machetanz, G., & Fitzgerald, J. C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00400 · Cited by 316
“There was improvement in the selective reminding test in the group receiving metformin but not in other cognitive or biomarker outcomes (108).”
Background
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives
Béard, E., Lengacher, S., Dias, S., Magistretti, P. J., & Finsterwald, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.825816 · Cited by 326
Metformin Use Associated With Reduced Risk of Dementia in Patients With Diabetes: A Systematic Review and Meta-Analysis
Campbell, J. M., Stephenson, M. D., de Courten, B., Chapman, I., Bellman, S. M., & Aromataris, E. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180263 · Cited by 292
“[52] performed regression analyses which showed 514”
BackgroundMethodInfluential
Alzheimer's disease and type 2 diabetes: a critical assessment of the shared pathological traits
Chatterjee, S., & Mudher, A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00383 · Cited by 270
Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications
Tumminia, A., Vinciguerra, F., Parisi, M., & Frittitta, L. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113306 · Cited by 263
“A recent pilot clinical trial in patients with MCI, randomly assigned to receive metformin or placebo for 12 months, showed that metformin improved cognition in individuals without diabetes [107].”
Background
A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies
Orr, M. E., Sullivan, A. C., & Frost, B. E. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.03.011 · Cited by 242
“treatment in patients with amnestic mild cognitive impairment at risk of developing [94_TD$DIFF] ype II diabetes reports an improvement in one, but not all, measures of cognition [59].”
Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases
Djajadikerta, A., Keshri, S., Tanasa, M. P., Prestil, R., Ryan, L., & Rubinsztein, D. C. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.035 · Cited by 244
“[55] Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, et al.”
Background
Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study
Samaras, K., Makkar, S. R., Crawford, J. D., Kochan, N. A., Wen, W. X., Draper, B., Trollor, J. N., Brodaty, H., & Sachdev, P. S. (2020) · Diabetes Care · doi:10.2337/dc20-0892 · Cited by 232
Insulin receptor in the brain: Mechanisms of activation and the role in the CNS pathology and treatment
Анатольевич, П. И., Costa-Nunes, J. P., Kasatkin, V. N., Veniaminova, E. A., Demchenko, A. G., Lyundup, A. V., Lesch, K., Ponomarev, E. D., & Strekalova, T. V. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12866 · Cited by 215
Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential
Zhang, W., Xu, C., Sun, J., Shen, H., Wang, J., & Yang, C. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.008 · Cited by 221
Mitochondrial dynamics and transport in Alzheimer's disease
Flannery, P. J., & Trushina, E. V. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2019.06.009 · Cited by 203
Epigenetic effects of metformin: from molecular mechanisms to clinical implications
Bridgeman, S. C., Ellison, G. C., Melton, P. E., Newsholme, P., & Mamotte, C. D. S. (2018) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13262 · Cited by 190
“Metformin may also be neuroprotective, with placebo-controlled randomized clinical trials reporting that metformin improves cognitive function in the cognitively impaired, such as those with Alzheimer’s disease.(24,25) Metformin was also suggested as an antiaging drug as early as the 1970s,(26) and is currently being…”
Background
Preventive and Therapeutic Strategies in Alzheimer's Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis
Plascencia‐Villa, G., & Perry, G. L. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8134 · Cited by 188
“A pilot study with 80 patients with MCI tested 1000 mg metformin twice per day for 12 months, showing differences in ADAS-Cog but no significant differences in memory, glucose uptake PET, or plasma Ab (106).”
Method
Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia
Fink, H. A., Jutkowitz, E., McCarten, J. R., Hemmy, L. S., Butler, M., Davila, H. W., Ratner, E. R., Calvert, C., Barclay, T. R., Brasure, M., et al. (2017) · Annals of Internal Medicine · doi:10.7326/m17-1529 · Cited by 205
“Diabetes Medications Among 8 eligible references (17, 20, 54–59), 4 unique trials had low to moderate risk of bias (17, 20, 54, 56, 59) (Part E of the Supplement).”
Background
Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., Gupta, D., & Edison, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101979 · Cited by 179
“A 12-month pilot trial in 80 overweight, amnestic MCI patients without T2DM revealed marginally significant improvements in recall of the Selective Reminding Test of verbal memory (Luchsinger et al., 2016).”
Intranasal Insulin for Alzheimer’s Disease
Hallschmid, M. (2021) · CNS Drugs · doi:10.1007/s40263-020-00781-x · Cited by 188
Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review
Yu, T.-W., Lane, H., & Lin, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158208 · Cited by 190
“After a 12-month intervention, the treated group showed a reduction in recall memory decline compared to the placebo group [84].”
BackgroundResult
Promoting Successful Cognitive Aging: A Ten-Year Update
Krivanek, T. J., Gale, S. A., McFeeley, B. M., Nicastri, C. M., & Daffner, K. R. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201462 · Cited by 189
Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies
Luo, A., Xie, Z., Wang, Y., Wang, X., Li, S., Yan, J., Zhan, G., Zhou, Z., Zhao, Y., & Li, S. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104642 · Cited by 169
Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes
Orkaby, A. R., Cho, K., Cormack, J. B., GAGNON, D. R., & Driver, J. A. (2017) · Neurology · doi:10.1212/wnl.0000000000004586 · Cited by 158
“Perhaps the most promising evidence comes from a recent pilot study of 80 older adults (mean age 65 years) with amnestic MCI who were randomized to metformin or placebo for 12 months and demonstrated improvement in total recall.(36) In contrast, we did not include individuals with MCI at baseline, although there were…”
Background
Is Alzheimer’s Disease Risk Modifiable?
Serrano‐Pozo, A., & Growdon, J. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad181028 · Cited by 169
“Interventional studies—Small pilot randomized placebo-controlled clinical trials have suggested that metformin [89,90], intranasal regular insulin [91,92], and intranasal longacting insulin (detemir) [92,93] may have a beneficial effect on cognition in patients with amnestic MCI or mild AD dementia.”
Metformin and ageing: improving ageing outcomes beyond glycaemic control
Valencia, W. M., Palacio, A., Tamariz, L., & Florez, H. (2017) · Diabetologia · doi:10.1007/s00125-017-4349-5 · Cited by 142
“Nonetheless,while thesestudieshave limitations, a recent pilot clinical trial substantiated their findings by showing thatmetformin improved cognition in individuals without diabetes [55].”
Aging, lifestyle and dementia
Wahl, D., Solon‐Biet, S. M., Cogger, V. C., Fontana, L., Simpson, S. J., Couteur, D. G. L., & Ribeiro, R. V. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104481 · Cited by 155
Protective properties of GLP‐1 and associated peptide hormones in neurodegenerative disorders
Hölscher, C. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15508 · Cited by 149
“The results from preclinical studies are mixed (Hölscher, 2020b) and a Phase II clini- cal trial that tested metformin in Alzheimer's disease patients showed no improvement (Luchsinger et al., 2016).”
Result
Mitochondrial complex I as a therapeutic target for Alzheimer's disease
Trushina, E. V., Trushin, S., & Hasan, M. F. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.11.003 · Cited by 131
Geroscience‐guided repurposing of FDA‐approved drugs to target aging: A proposed process and prioritization
Kulkarni, A. S., Aleksić, S., Berger, D. M., Sierra, F., Kuchel, G. A., & Barzilai, N. (2022) · Aging Cell · doi:10.1111/acel.13596 · Cited by 132
“For instance, the doses of rapamycin or rapalogs used both in mice (ITP studies) and human (Mannick et al, 2014; Mannick et al, 2018; Mannick et al, 2021) studies are several times lower than doses commonly used in clinical practice to induce immunotolerance in transplant patients, or as an…”
BackgroundInfluential
Brain Metabolic Alterations in Alzheimer’s Disease
Ardanaz, C. G., Ramírez, M. J., & Solas, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073785 · Cited by 135
“Within this last group of insulin modulator drugs, some of them have shown promising results in the treatment of AD, especially metformin [261,262], thiazolidinediones [263–266], SGLT2 inhibitors [267] and glucose like peptide-1 (GLP-1) analogues [268–272].”
Background
The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth
Amin, S., Lux, A. L., & O'Callaghan, F. J. (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13780 · Cited by 128
“However, this study by Luchsinger et al has suggested that metformin also improves cognition in individuals without diabetes.(14)”
Result
Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease
Hölscher, C. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00088 · Cited by 122
“Treatment for 12 months only showed a very small improvement in a recall test with no changes in ADAScog or in 18FDG-PET brain scans (Luchsinger et al., 2016).”
Background
Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin
Ayoub, R., Ruddy, R. M., Cox, E., Oyefiade, A., Derkach, D., Laughlin, S., Ades-aron, B., Shirzadi, Z., Fieremans, E., MacIntosh, B. J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0985-2 · Cited by 117
Preventing dementia? Interventional approaches in mild cognitive impairment
Lissek, V. J., & Boris Suchan, A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.12.022 · Cited by 127
Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts
Weinstein, G., Davis‐Plourde, K. L., Conner, S. C., Himali, J. J., Beiser, A., Lee, A., Rawlings, A. M., Sedaghat, S., Ding, J., Moshier, E. L., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212293 · Cited by 117
AMPK: A bridge between diabetes mellitus and Alzheimer's disease
Chen, M., Huang, N., Liu, J., Huang, J., Shi, J., & Jin, F. J. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.113043 · Cited by 119
Inflammation and Insulin Resistance as Risk Factors and Potential Therapeutic Targets for Alzheimer’s Disease
Vinuesa, Á., Pomilio, C. J., Gregosa, A., Bentivegna, M., Presa, J., Bellotto, M., Saravia, F., & Beauquis, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.653651 · Cited by 117
Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice
Chen, Y., Zhao, S., Fan, Z., Li, Z., Zhu, Y., Shen, T., Li, K., Yan, Y., Tian, J., Liu, Z., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00761-9 · Cited by 111
“An interventional study found that, in overweight patients aged 55 to 90 years with amnestic mild cognitive impairment, those receiving metformin for 12 months had better performance in the selective reminding test than those receiving placebo [17].”
Metformin role in Parkinson’s disease: a double-sword effect
Alrouji, M., Al-Kuraishy, H. M., Al-Gareeb, A. I., Ashour, N. A., Jabir, M. S., Negm, W. A., & Batiha, G. E. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04771-7 · Cited by 104
“Further, prolonged use of metformin for 12 months accelerates cognitive functions in T2DM patients with mild cognitive impairment [55, 56].”
Insulin Resistance as a Therapeutic Target in the Treatment of Alzheimer's Disease: A State-of-the-Art Review
Benedict, C., & Grillo, C. A. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00215 · Cited by 101
“The beneficial effects of metformin are also supported by other study that showed that 1 year of treatment improved total recall compare to baseline in overweight/obese patients with MCI (Luchsinger et al., 2016).”
Result
Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis
Ping, F., Jiang, N., & Li, Y. (2020) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2020-001370 · Cited by 97
Role of insulin receptor substance-1 modulating PI3K/Akt insulin signaling pathway in Alzheimer’s disease
Zheng, M., & Wang, P. (2021) · 3 Biotech · doi:10.1007/s13205-021-02738-3 · Cited by 110
Challenges in developing Geroscience trials
Rolland, Y., Sierra, F., Ferrucci, L., Barzilai, N., de Cabo, R., Mannick, J. B., Oliva, A. A., Evans, W. J., Angioni, D., Barreto, P. D. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39786-7 · Cited by 98
Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
Buccellato, F. R., D’Anca, M., Tartaglia, G. M., Del Fabbro, M., Scarpini, E., & Galimberti, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813900 · Cited by 94
“Glucose metabolism amelioration in the Central Nervous System (CNS) is supposed to improve the cognitive decline of early and late amnestic Mild Cognitive Impairment patients or prevent the cognitive decline in obese people [3,105,106].”
Background
Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer's disease, and the role APOE carrier status
Wu, C., Ouk, M., Wong, Y. Y., Anita, N. Z., Edwards, J. D., Yang, P., Shah, B. R., Herrmann, N., Lanctôt, K. L., Kapral, M. K., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12161 · Cited by 94
Enhancing autophagy in Alzheimer's disease through drug repositioning
Eshraghi, M., Ahmadi, M., Afshar, S., Lorzadeh, S., Adlimoghaddam, A., Rezvani Jalal, N., West, R., Dastghaib, S., Igder, S., Torshizi, S. R. N., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108171 · Cited by 89
Metformin: An old drug against old age and associated morbidities
Salvatore, T., Pafundi, P. C., Morgillo, F., Liello, R. D., Galiero, R., Nevola, R., Marfella, R., Monaco, L., Rinaldi, L., Adinolfi, L. E., et al. (2020) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2020.108025 · Cited by 88
Deciphering the Roles of Metformin in Alzheimer’s Disease: A Snapshot
Liao, W., Xu, J., Li, B., Ruan, Y., Li, T., & Liu, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.728315 · Cited by 84
“found that metformin 1,000 mg twice a day for 12 months could result in greater improvement than placebo use in selective reminding test (SRT) as well as a statistically nonsignificant increase of plasma Aβ42 in overweight patients with amnestic mild cognitive impairment (aMCI) (Luchsinger et al., 2016).”
Background
Impact of pharmacological treatment of diabetes mellitus on dementia risk: systematic review and meta-analysis
McMillan, J. M., Mele, B. S., Hogan, D. B., & Leung, A. A. (2018) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2018-000563 · Cited by 80
“In one clinical trial, the use of metformin in newly treated patients with DM reduced the risk of MCI.49 Our systematic review found highly variable results across studies.”
Result
Type 2 diabetes mellitus and cognitive function: understanding the connections
Dao, L., CHOI, S. E., & Freeby, M. (2022) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000783 · Cited by 82
Remembering your A, B, C's: Alzheimer's disease and ABCA1
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76
Metformin, lifestyle intervention, and cognition in the Diabetes Prevention Program Outcomes Study
Luchsinger, J. A., Ma, Y., Christophi, C. A., Florez, H., Golden, S. H., Hazuda, H., Crandall, J., Venditti, E., Watson, K., Jeffries, S., et al. (2017) · Diabetes Care · doi:10.2337/dc16-2376 · Cited by 75
“in people with mild cognitive impairment showed that metformin treatment improved memory after 12 months compared with placebo (30).”
BackgroundSelf-citation
A story of metformin-butyrate synergism to control various pathological conditions as a consequence of gut microbiome modification: Genesis of a wonder drug?
Maniar, K., Moideen, A., Mittal, A., Patil, A., Chakrabarti, A., & Banerjee, D. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.12.003 · Cited by 75
“A recent pilot study[372] exploring the use of metformin in previously untreated diabetic patients showed a trend favoring”
Background
Pharmacotherapy of Alzheimer’s Disease: Seeking Clarity in a Time of Uncertainty
Ibrahim, N. H., Yahaya, M. F., Mohamed, W. M. Y., Teoh, S. L., Hui, C. K., & Kumar, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00261 · Cited by 77
Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta
Teo, E., Ravi, S., Barardo, D., Kim, H.-S., Fong, S., Cazenave-Gassiot, A., Tan, T. Y., Ching, J., Kovalik, J.-P., Wenk, M. R., et al. (2019) · eLife · doi:10.7554/elife.50069 · Cited by 72
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
Mone, P., Gambardella, J., Pansini, A., Donato, A. D., Martinelli, G., Boccalone, E., Matarese, A., Frullone, S., & Santulli, G. (2021) · Cells · doi:10.3390/cells10082115 · Cited by 72
State of the science on brain insulin resistance and cognitive decline due to Alzheimer's disease
Rhea, E. M., Leclerc, M., Yassine, H. N., Capuano, A. W., Tong, H., Petyuk, V. A., Macauley, S. L., Fioramonti, X., Carmichael, O., Calon, F., et al. (2023) · Aging and disease · doi:10.14336/ad.2023.0814 · Cited by 70
Neuromodulatory effects of anti-diabetes medications: A mechanistic review
Yaribeygi, H., Ashrafizadeh, M., Henney, N. C., Sathyapalan, T., Jamialahmadi, T., & Sahebkar, A. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104611 · Cited by 71
Antidiabetic Drugs in the Treatment of Alzheimer’s Disease
Michailidis, M., Tata, D. Α., Μoraitou, D., Kavvadas, D., Karachrysafi, S., Papamitsou, T., Vareltzis, P. K., & Papaliagkas, V. T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094641 · Cited by 71
“, 2016 [43] Metformin MCI Significant improvement in verbal memory.”
Background
The Emerging Roles of Autophagy in Human Diseases
Lei, Y., & Klionsky, D. J. (2021) · Biomedicines · doi:10.3390/biomedicines9111651 · Cited by 68
“Besides the chemicals tested in the mouse model, lithium and metformin are being used in clinical trial in patients with mild cognitive impairment, which is associated with high risk of PD, and the studies indicate that these two autophagy-stimulating molecules can attenuate cognitive decline in these patients [287,28…”
Background
Bridging Type 2 Diabetes and Alzheimer's Disease: Assembling the Puzzle Pieces in the Quest for the Molecules With Therapeutic and Preventive Potential
de Matos, A. M., Macedo, M. P., & Rauter, A. P. (2017) · Medicinal Research Reviews · doi:10.1002/med.21440 · Cited by 68
Metformin, Cognitive Function, and Changes in the Gut Microbiome
Rosell-Díaz, M., & Fernández‐Real, J. M. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad029 · Cited by 68
Diabetes: a tipping point in neurodegenerative diseases
Santiago, J. A., Karthikeyan, M., Lackey, M., Villavicencio, D., & Potashkin, J. A. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.09.005 · Cited by 65
Insulin mediated novel therapies for the treatment of Alzheimer's disease
Dubey, S. K., Lakshmi, K. K., Krishna, K. V., Agrawal, M., Singhvi, G., Saha, R. N., Saraf, S., Saraf, S., Shukla, R., & Alexander, A. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117540 · Cited by 62
Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease
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A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol
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BackgroundSelf-citation
Clinical Trials of New Drugs for Vascular Cognitive Impairment and Vascular Dementia
Linh, T. T. D., Hsieh, Y., Huang, L., & Hu, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911067 · Cited by 57
“However, only two RCTs on metformin have revealed its advantages over a placebo in terms of cognitive function and cerebral blood flow [75,76].”
Background
Antidiabetic Drugs in Alzheimer’s Disease: Mechanisms of Action and Future Perspectives
Femminella, G. D., Bencivenga, L., Petraglia, L., Visaggi, L., Gioia, L., Grieco, F. V., de Lucia, C., Komici, K., Corbi, G., Edison, P., et al. (2017) · Journal of Diabetes Research · doi:10.1155/2017/7420796 · Cited by 57
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Exercise mimetics: a novel strategy to combat neuroinflammation and Alzheimer’s disease
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“Another study [405] used data from a prospective cohort data of elderly Latinos in the US to examine the effect of metformin on cognition.”
Method
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Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders
Chen, Q., Cao, T., Li, N., Zeng, C., Zhang, S., Wu, X., Zhang, B., & Cai, H. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.667874 · Cited by 50
“In patients with amnestic mild cognitive impairment or non-diabetes subjects with mild cognitive impairment or mild dementia due to AD, metformin treatment was associated with promising cognitive enhancement(Luchsinger et al., 2016; Koenig et al., 2017).”
Background
Clusterin and Its Role in Insulin Resistance and the Cardiometabolic Syndrome
Wittwer, J. A., & Bradley, D. P. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.612496 · Cited by 51
Status and future directions of clinical trials in Alzheimer's disease
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Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia
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Intranasal metformin treatment ameliorates cognitive functions via insulin signaling pathway in ICV-STZ-induced mice model of Alzheimer's disease
Kazkayası, İ., Telli, G., Nemutlu, E., & Uma, S. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120538 · Cited by 50
Metformin improves cognitive impairment in patients with schizophrenia: associated with enhanced functional connectivity of dorsolateral prefrontal cortex
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“’s (2018) study and is different from the results of other previous studies (Herath et al., 2016; Hervas et al., 2017; Hsu et al., 2011; Luchsinger et al., 2016; Ng et al., 2014; Samaras et al., 2020; Zhang et al., 2020; Zhou et al., 2020).”
BackgroundMethodResultInfluential
Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner
Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., & Chen, X. (2019) · The FASEB Journal · doi:10.1096/fj.201802718r · Cited by 44
Mitochondrial DNA and Inflammation in Alzheimer’s Disease
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Metabolic determinants of Alzheimer’s disease: A focus on thermoregulation
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New treatment approaches for Alzheimer’s disease: preclinical studies and clinical trials centered on antidiabetic drugs
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BackgroundMethod
Therapeutic approaches for improving cognitive function in the aging brain
Chen, L., Jiao, J., & Zhang, Y. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1060556 · Cited by 42
“5% of participants, and no serious adverse events occurred (Luchsinger et al., 2016).”
Background
Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment
Poor, S. R., Ettcheto, M., Cano, A. C., Sánchez‐López, E., Manzine, P. R., Olloquequi, J., Camins, A., & Javan, M. (2021) · Pharmaceuticals · doi:10.3390/ph14090890 · Cited by 41
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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

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

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