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Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial
Open accessAbstract
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.
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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.
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Claims the paper makes
39 Own result · 36 Not checked yet · 22 Own method · 4 Own interpretation · 4 No basis given
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
“The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Differences for other outcomes were not significant.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Compliance with metformin and adverse events · plain
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
“Metformin could not be tolerated by 7.5% of participants”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Abstract
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Changes in the clinical outcomes · plain
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
plainn = 40- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
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
“One person in the placebo group and none in the metformin group converted to dementia.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 differences in delayed recall of the ADAS-cog (0.7±1.8 for metformin vs. 0.0± 2.5 for placebo; p = 0.35).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The highest metformin dose (1000 mg twice a day) was associated with a statistically significant increase of 5.3±10.0 more words in total recall of the SRT (p = 0.03) compared to those in the placebo group and those who could not tolerate metformin.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 differences for the ADAS-Cog in any of the strata.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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
plainn = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § Compliance with metformin and adverse events · plain
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
“We found in a pilot study that conducting a randomized trial of metformin in persons with AMCI was feasible and safe.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Crude analyses showed a greater improvement in the SRT in the metformin group, but the difference for the ADAS-Cog favored the placebo group.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Weight decreased more in the metformin group (-2.7 ± 6.4 Kg) compared with the placebo group (-1.6 ± 4.5 Kg) but this difference was not statistically signficant (p = 0.63).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes of metabolic measures by randomization arms
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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 differences between metformin and placebo in changes in digit span backwards, the neuropsychiatric inventory, the MMSE, paragraph recall, or CGIC-MCI (Supplemental table 1).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Fasting insulin increased appreciably more in the placebo group compared with the metformin group as expected, and this difference was close to statistical significance (13.8 vs. 4.7 IU/ml; p = 0.09).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes of metabolic measures by randomization arms
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“The results were similar for delayed recall of the SRT, in which the gain in words was higher in the metformin group (2.3 ± 2.5) compared to the placebo group (1.3 ± 2.3) and was close to statistical significance (p=0.06).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“We also found preliminary evidence of efficacy for one of the primary outcomes, total recall in the Selective Reminding Test, but not the other, the ADAS-Cog, after adjusting for the baseline difference in the ADAS-Cog.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Secondary ROIs including hippocampus (2.4 ± 4.7% vs. 1.0 ± 5.1%; p =0.73), para-hippocampus (3.3 ± 5.5% vs. 2.0 ± 5.1%; p =0.76), and entorhinal cortex (5.3± 9.0% vs. 1.3 ± 6.0; p =0.16) favored metformin but were not statistically significant.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in Biomarker outcomes
plainn = 40- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“HbA1c decreased modestly more in the metformin group (-0.3 ± 0.7 %) compared with the placebo group (- 0.2 ± 0.5), but this difference was not statistically significant (p=0.64).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes of metabolic measures by randomization arms
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Differences between metformin and placebo in changes in the primary and exploratory biomarker outcomes were not significantly different but the direction of the difference modestly favored metformin and supported the finding for the SRT.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Post hoc analyses suggest that the benefit on the SRT total recall is higher with the highest metformin dose, among younger subjects, among those without APOE-ε4, among those with the lower HbA1c, and those with the highest baseline fasting insulin.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Both the SRT and ADAS-COG scores improved in the placebo and metformin groups (increases in SRT total recall, decreases in ADAS-COG scores).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“None of the differences in changes in plasma Aβ-42 were statistically significant. Plasma Aβ-42 increased in the metformin group (0.69 ± 18.5 pg/ml) and decreased in the placebo group (-4.40 ± 23.51 pg/ml; p=0.3).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in Biomarker outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Metformin showed better performance compared with placebo in younger persons, those without APOE-ε4, those with lower HbA1c, and those with higher insulin levels.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in the clinical outcomes
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“hsCRP, a measure of inflammation and vascular risk [63], and a correlate of memory impairment in our center[64] decreased in the metformin group and increased in the placebo group (-0.3 vs. 1.0 mg/dl; p = 0.07).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes of metabolic measures by randomization arms
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“we found a result benefiting metformin for the the SRT but not for the ADAS-Cog.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The side effects and safety for metformin in our trial were similar to published research and clinical experience.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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
“The difference for the ADAS-cog favoring placebo dissapeared after adjusting for the significant differences in baseline ADAS-cog, while the differences in the SRT persisted.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These challenges included a long recruitment period due in part to a large number of subjects needed to be screened”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“our study showed improvements in both clinical outcomes, contrary to the idea that cognition declines with time.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
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
“This study was approved by the Institutional Review Board of Columbia University Medical Center (AAAC7231) and was registered in ClinicalTrials.gov (ID NCT00620191).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“Intra- and inter-assay coefficients of variation are 4.7% and 8.2%, respectively.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Other measures
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“65 subjects (81%) completed 12 months, 6 subjects (7.5 %) completed 9 months, and 9 subjects (11.2%) had less than 9 months of follow-up.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Participant characteristics
plainn = 65- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“This study was a double-blind placebo-controlled randomized pilot trial of metformin 1000 mg twice a day vs. matching placebo for 12 months in 80 subjects with AMCI.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods
plainn = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“it was powered to detect a large difference (0.75 standard deviations) in the change in the outcomes at 12 months with a sample size of 30 persons per group (Total 60 groups). We obtained supplementary funding and increased the sample size from 60 to 80 participants.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plainn = 80- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“However, given the pilot nature of our study with a relatively small sample size and the potential for chance findings, our preliminary evidence of efficacy should be taken with caution.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
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
“Allocation concealment was maintained by randomly alternating block sizes.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 test–retest reliability of the measurement of plasma Aβ42 is excellent (Cronbach's α coefficient = 0.91).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Outcomes
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“No interim analyses were planned or conducted during the conduct of the clinical trial.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Also stated in: § Statistical Analyses · plain
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 only statistically significant difference between the groups at baseline (Table 2) was the ADAS-Cog score, which was lower (better) in the metformin group.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Participant characteristics
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Initial analyses were conducted blinded to true treatment allocation. Treatment unblinding was conducted after analyses were checked for quality.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“Compliance with metformin was as follows: 7.5% stopped metformin but continued in the study following ITT, 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 > Results > Compliance with metformin and adverse events
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Imputation with last-observation-carried-forward (LOCF) was used to account for missing follow-up data.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Follow-up MRI and PET were completed in 33 out of 40 participants (15 in the metformin group, 18 in the placebo group, 82.5% completion overall).”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Results > Changes in Biomarker outcomes
plainn = 40- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“To balance factors that may influence treatment outcome, randomization was stratified and blocked. The only stratification variable was the presence or absence of APOE-ε4 genotype.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. 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
“Analysis of Covariance (ANCOVA) was used to compare outcomes between the treatment groups following an Intent-to-treat (ITT) approach adjusting for variables that were different at baseline if necessary.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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 coordinators conducting outcomes assessments were blinded from these data.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 results of post-hoc analyses are are subject to chance.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It seems safe and feasible to conduct a randomized trial of metformin among persons with MCI although we encountered important challenges.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we cautiously believe that there are preliminary findings justify the conduct of larger clinical trial.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
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
“We acknowledge that our results must be interpreted with caution because of the inconsistency of the results for the SRT and ADAS-cog”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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].”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [105]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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).”
From Metformin as a tool to target aging (2016) · cites this paper as Luchsinger et al., 2016
Experimental — accuracy not yet measured
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods
“Half the sample (40 participants) were invited to participate in a brain imaging sub-study.”
§ Metformin in Amnestic Mild Cognitive Impairment: results of a pilot randomized placebo controlled clinical trial > Materials and Methods
“All participants were invited to undergo brain imaging at baseline and after the 12 month visit and were selected if they agreed to undergo brain imaging and if they had no exclusion criteria for brain imaging.”
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“However, as the main side effect of metformin, some of the patients experienced gastrointestinal symptoms in a pilot randomized placebo-controlled clinical trial evaluating the impact of metformin on amnestic mild cognitive impairment [12].”
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Metformin: Beyond Diabetes Management to Neuroprotection and Cognitive Enhancement
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“Larger studies, preferably designed specifically to assess the relationship, are needed to evaluate the effect of metformin on functional outcomes in PWH. 19–21 The hypothesis that metformin may improve functional outcomes among PWH is scientifically justified.”
Metformin Use Beyond Diabetes: Reducing Cardiovascular Events In The Healthy Elderly
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“In a 12-month trial with non-diabetic individuals with mild cognitive impairment, metformin showed some promise in memory outcomes, but not in other key measures [265], leading to a further ongoing trial (NCT04098666).”
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“For instance, in one clinical trial (NCT00620191), patients with AD treated with metformin showed a statistically significant improvement on the selective reminding test (Luchsinger et al., 2016).”
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“…2 (TREM2) (Wolfe et al. 2018), astrocyte modulators, for example, P2Y1 puri-noreceptors (P2Y1R) inhibitors (Reichenbach &Delekate, 2018), via insulin resistance management, i.e. Metformin (Luchsinger et al. 2016), and microbiome therapy, for example, sodium oligomannate (GV-971) (Wang et al. 2019).”
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“These computational fi ndings are consistent with experimental and preliminary clinical evidence, including observational studies and randomized clinical trials, suggesting thatmetforminmay reducetheriskof AD and comorbid AD in individuals with DM2 while also enhancing cognitive performance 52 – 57 .”
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“96 Similarly, another RCT in 20 non-diabetic patients with mild cognitive impairment (MCI) or early AD reported that metformin treatment resulted in signi fi cantly better executive function compared to placebo.”
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Cognitive Enhancers and Treatments for Alzheimer’s Disease
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Cardiovascular and Retinal Vascular Changes in Preclinical Alzheimer's Disease
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Vascular Risk Factors and Cognitive Function
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Pharmacotherapy of Alzheimer's disease: A thorny road to success
Ibrahim, N. H., Kumar, J., & Mohamed, W. M. Y. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15702-8.00027-0
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Dawood, S. H., & Zavadsky, S. P. (2024) · Glavvrač (Chief Medical Officer) · doi:10.33920/med-03-2412-13
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A Review on the Association Between Metformin Use and Different Types of Anemia
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Oxidative stress in brain accelerates the onset of neurodegeneration in hyperglycemic individuals
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Self-citationAlzheimer’s disease: diabetes of the brain
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“This pattern is concordant with randomized evidence demonstrating that intensive blood pressure control reduces incident MCI among individuals at elevated vascular risk 14 and metformin improves memory performance 36 .”
Metformin promotes broad neuroprotection and proteostatic resilience via rngo/DDI2 stabilisationPreprint
Xu, D., Kim, Y., Anoar, S., Jiang, X., Alatza, A., Chiozzi, R. Z., Thalassinos, K., Isaacs, A. M., Lashley, T., Wray, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.11.705245
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“This aligns with prior small-scale trials of metformin in AD dementia patients, 28,29 which showed no signi fi cant alterations in A β or tau biomarkers in CSF or plasma, despite trends toward cognitive bene fi ts. Preclinical studies have likewise found that metformin treatment improved cognitive de…”
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Froes, B. R., Pina, J. G., Alves, M. D. M., Mançano, A. S. F., Cardoso, F. C., & Sciani, J. M. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18060696 · Cited by 1
“For example, metformin has been tested in patients with amnestic mild cognitive impairment, although no significant differences were observed in cognitive scores or plasma A β 42 levels [42].”
Belayneh, Y. M. (2026) · Annals of Neurosciences · doi:10.1177/09727531261470255
Tianci, M., Yongyi, L., Ding, Y., Liu, S., Gao, C., Li, X., Tong, Z., & Yan, L. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1921485
Effect of metformin treatment on brain 18F-FDG uptake: a translational study
de la Rosa, R. F., Domingo, G. C., Nespral, P., Marcos-Macías, E., Vaillant, M., García‐García, L., Pozo, M. A., Matías‐Guiu, J. A., Cabrera‐Martín, M. N., Brackhan, M., et al. (2026) · Frontiers in Radiology · doi:10.3389/fradi.2026.1917175
Metadata
- 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
- 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
- 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.
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