Metformin in Alzheimer's Dementia Prevention
Phase: PHASE2
Conditions: Mild Cognitive Impairment
Sponsor: Columbia University

Metformin 
 in Alzheimer’s dementia Prevention (MAP) 
Protocol Number, Columbia University: AAAS6912 
Protocol Number, Johns Hopkins University: JHUSIRB00000013 
National Clinical Trial (NCT) Identified Number:  NCT04098666 
Principal Investigator: José A. Luchsinger, M.D. 
Sponsor: Columbia University Irving Medical Center 
Funded by: National Institute on Aging (R01 AG062624) 
Version Number:  v2.0 
May 21, 2024 
 

Metformin in Alzheimer’s dementia Prevention (MAP) 
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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ...................................................................................................................... 5 
1 
PROTOCOL SUMMARY ........................................................................................................................ 5 
1.1 
Synopsis ....................................................................................................................................................... 5 
1.2 
Schema ........................................................................................................................................................ 7 
1.3 
Study duration ............................................................................................................................................ 8 
2 
INTRODUCTION ................................................................................................................................... 8 
2.1 
Study Rationale .......................................................................................................................................... 8 
2.2 
Background ................................................................................................................................................. 9 
2.2.1 
Peripheral hyperinsulinemia – increased risk of Alzheimer’s ................................................ 9 
2.2.2 
Metformin for Alzheimer’s prevention .................................................................................. 9 
2.2.3 
Overall supporting evidence ................................................................................................ 11 
2.2.4 
Brain imaging diagnosis of Alzheimer’s disease .................................................................. 11 
2.2.5 
Blood-based diagnosis of Alzheimer’s dementia ................................................................. 12 
2.2.6 
COVID-19 and cognition ....................................................................................................... 13 
2.2.7 
Preliminary data  ............................................................................................................... 13 
2.3 
Risk/Benefit Assessment ......................................................................................................................... 21 
2.3.1 
Known Potential Risks and their mitigation......................................................................... 21 
2.3.2 
Potential Benefits  ............................................................................................................... 26 
3 
OBJECTIVES AND ENDPOINTS ........................................................................................................... 27 
4 
STUDY DESIGN .................................................................................................................................. 28 
4.1 
Overall Design .......................................................................................................................................... 28 
4.2 
Scientific Rationale for Study Design .................................................................................................... 29 
4.3 
Justification for Dose ............................................................................................................................... 29 
4.4 
End of Study Definition ........................................................................................................................... 29 
5 
STUDY POPULATION ......................................................................................................................... 29 
5.1 
Inclusion Criteria ...................................................................................................................................... 29 
5.2 
Exclusion Criteria ..................................................................................................................................... 30 
5.3 
Lifestyle Considerations .......................................................................................................................... 32 
5.4 
Screen Failures ......................................................................................................................................... 32 
5.5 
Strategies for Recruitment and Retention ........................................................................................... 32 
6 
STUDY INTERVENTION ...................................................................................................................... 33 
6.1 
Study Intervention(s) Administration ................................................................................................... 33 
6.1.1 
Study Intervention Description ............................................................................................ 33 
6.1.2 
Dosing and Administration .................................................................................................. 33 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................... 33 
6.2.1 
Acquisition and accountability ............................................................................................. 34 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 34 
6.2.3 
Product Storage and Stability .............................................................................................. 34 
6.2.4 
Preparation…………. .............................................................................................................. 34 
6.3 
Measures to Minimize Bias: Randomization and Blinding................................................................. 34 

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6.4 
Study Intervention Compliance ............................................................................................................. 35 
6.5 
Concomitant Therapy .............................................................................................................................. 35 
6.5.1 
Rescue Medicine  ............................................................................................................... 35 
7 
Discontinuation of Study Intervention and Withdrawal of Participant ............................................ 35 
7.1 
Discontinuation of Study Intervention ................................................................................................. 35 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................................................. 36 
7.3 
Lost to Follow-Up ..................................................................................................................................... 36 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................ 36 
8.1 
Efficacy Assessments ............................................................................................................................... 38 
8.2 
Safety and Other Assessments .............................................................................................................. 43 
8.3 
Adverse Events and Serious Adverse Events ....................................................................................... 43 
8.3.1 
Definition of Adverse Events (AE) ........................................................................................ 43 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 44 
8.3.3 
Classification of an Adverse Event ....................................................................................... 44 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................................... 45 
8.3.5 
Adverse Event Reporting ..................................................................................................... 46 
8.3.6 
Serious Adverse Event Reporting......................................................................................... 46 
8.3.7 
Reporting Events to Participants ......................................................................................... 47 
8.3.8 
Events of Special Interest ..................................................................................................... 47 
8.3.9 
Reporting of Pregnancy ....................................................................................................... 47 
8.4 
Unanticipated Problems ......................................................................................................................... 48 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................................... 48 
8.4.2 
Unanticipated Problem Reporting ....................................................................................... 48 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................................. 49 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................ 49 
9.1 
Statistical Hypotheses ............................................................................................................................. 49 
9.2 
Sample Size Determination .................................................................................................................... 50 
9.3 
Populations for Analyses ........................................................................................................................ 51 
9.4 
Statistical Analyses .................................................................................................................................. 51 
9.4.1 
General Approach  ............................................................................................................... 51 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................................... 51 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................................ 53 
9.4.4 
Safety Analyses………. ........................................................................................................... 53 
9.4.5 
Baseline Descriptive Statistics ............................................................................................. 53 
9.4.6 
Planned Interim Analyses .................................................................................................... 53 
9.4.7 
Sub-Group Analyses ............................................................................................................. 53 
9.4.8 
Tabulation of Individual participant Data ............................................................................ 53 
9.4.9 
Exploratory Analyses ............................................................................................................ 54 
9.4.10 Decision to move to phase IIII trial ...................................................................................... 54 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS........................................ 54 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................................. 54 
10.1.1 Informed Consent Process ................................................................................................... 54 
10.1.2 Study Discontinuation and Closure ...................................................................................... 56 

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10.1.3 Confidentiality and Privacy .................................................................................................. 56 
10.1.4 Future Use of Stored Specimens and Data .......................................................................... 57 
10.1.5 Key Roles and Study Governance ........................................................................................ 57 
10.1.6 Safety Oversight 
 ............................................................................................................... 59 
10.1.7 Clinical Monitoring ............................................................................................................... 59 
10.1.8 Quality Assurance and Quality Control ................................................................................ 60 
10.1.9 Data Handling and Record Keeping ..................................................................................... 60 
10.1.10 Protocol Deviations .............................................................................................................. 64 
10.1.11 Publication and Data Sharing Policy .................................................................................... 65 
10.1.12 Conflict of Interest Policy ..................................................................................................... 66 
10.2 
Abbreviations ........................................................................................................................................... 66 
10.3 
Protocol Amendment History ................................................................................................................ 69 
11 
REFERENCES ...................................................................................................................................... 70 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Johns Hopkins Medicine (JHM) Institutional Review Board (IRB), which is acting as the 
single IRB (sIRB) of record for review and approval of this study. JHM sIRB approval must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and approval by 
the sIRB before the changes are implemented to the study. In addition, all changes to the consent form 
will be sIRB-approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Metformin in Alzheimer’s dementia Prevention (MAP) 
 
Study Description: 
Up to Protocol version 1.8, MAP was a 24-month phase II/III 1:1 randomized 
clinical trial of extended-release metformin (Glucophage XR [reduced 
mass]) 2000 mg (in 500 mg tablets) vs. matching placebo among 370 
persons with amnestic mild cognitive impairment without diabetes in the 
prevention of cognitive decline among persons at risk for Alzheimer’s 
dementia.  Participants were assessed every six months for a total of 5 visits 
(baseline and months 6, 12, 18, and 24). Up to 186 participants were 
planned to undergo brain magnetic resonance imaging (MRI) at baseline 
and after the 24 months visit.  Up to 186 participants were also expected to 
undergo amyloid (18F-florbetaben) positron emission tomography (PET) 
and tau (18F-MK-6240) PET at baseline and after the 24 months visit, 
independently of the MRI. For protocol version 1.9, the follow-up duration 
was decreased to 18 months (4 visits), and the sample size was decreased 
to 326, based on a reconsideration of the pilot data and assumptions 
supporting the original design. Follow-up and PET will be completed after 
the 18-month visit.  
Objectives: 
Primary Objective:  To test the efficacy of metformin in the prevention of 
cognitive decline associated with Alzheimer’s dementia, we will compare 
changes over 18 months in verbal memory performance, measured with the 
Total Recall Score of the Free and Cued Selective Reminding Test (FC-SRT)  
 
Secondary Objectives:  1) Examine changes in global cognitive performance 
measured with the Alzheimer’s Disease Cooperative Study, Preclinical 

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Alzheimer Cognitive Composite (ADCS-PACC); 2) Compare changes in 
neurodegeneration (cortical thickness) ascertained on MRI between 
metformin and placebo; 3) Compare changes in cerebrovascular disease 
(white matter hyperintensities) ascertained on MRI  between metformin 
and placebo; 4) Compare changes in whole brain amyloid β (Aβ) 
standardized uptake value ratio (SUVR) and in incident amyloid positivity 
from baseline to 18 months between the metformin and placebo arms ; 5) 
Compare changes in tau SUVR in a composite brain region comprising 
medial and inferolateral temporal cortex from baseline to 18 months 
between the metformin and placebo arms; 6) Compare changes in plasma 
Alzheimer’s disease (AD) biomarkers over 18-month follow-up between 
metformin and placebo; 7) To examine APOE-ε4 genotype and COVID-19 
history as a modifier of the efficacy of metformin. 
Endpoints: 
The primary endpoint is changes from baseline to 18 months in verbal 
memory performance, measured with the Total Recall Score of the FC-SRT, 
between the metformin and placebo arms, following an intent to treat (ITT) 
approach. The secondary endpoints are 1) changes in global cognitive 
performance, measured with the Alzheimer’s Disease Cooperative Study 
Preclinical Alzheimer Cognitive Composite (ADCS-PACC); 2) changes in 
neurodegeneration, ascertained as cortical thickness in areas affected by 
AD on brain MRI; 3) changes in cerebrovascular disease, ascertained as 
white matter hyperintensities (WMH) volume on brain MRI; 4) Changes in 
whole brain amyloid ß (Aß) SUVR and in incident amyloid positivity; 5) 
Changes in tau SUVR in a composite brain region comprising medial and 
inferolateral temporal cortex; 6) Changes in plasma AD biomarkers. The FC-
SRT and ADCS-PACC, and the plasma AD biomarkers will be measured 4 
times in the study (baseline and months 6, 12, and 18). The brain imaging 
measures will be measured twice, at baseline and 18 months. We will also 
explore incident amyloid positivity at 18 months as determined by a cutoff 
of Aß from PET equal to 24 centiloids. 
Study Population: 
The target sample are 326 (163 per arm) men and women aged 55 years to 
90 years, with early or late amnestic mild cognitive impairment (aMCI), 
without dementia, without diabetes, with a body mass index (BMI) of 20 
k/m2 or higher, not taking metformin, without contraindications to 
metformin use, and not taking any cognitive enhancers or medications that 
interfere with cognition. Biomarkers will not be used for the definition of 
aMCI. We will use the early aMCI and late aMCI criteria from the Alzheimer’s 
Disease Neuroimaging Initiative (ADNI). The eligibility criteria, recruitment 
and retention strategies are described in detail in section 2.2 (Eligibility 
criteria). Persons without contraindications to MRI may undergo MRI, but 
inability or unwillingness to undergo MRI will not be a reason for exclusion. 
Participation will require the availability of a study partner (a person who 
knows the participant well), in order to answer questions about the 
participant in person or via telephone.  Persons without contraindication to 
PET will also be invited to undergo amyloid and tau PET, independent of 
MRI.  

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Phase: 
II /III 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
There will be multiple sites in the United States chosen for their capacity to 
recruit, previous experience in Alzheimer’s disease clinical trials, previous 
experience in National Institute on Aging’s (NIA’s) Alzheimer’s Disease 
Cooperative Study (ADCS), and their affiliation with a local Clinical 
Translational Science Award (CTSA) funded by the National Center for 
Advancing Translational Sciences (NCATS).   
Description of Study  
Intervention: 
The trial will be preceded by a screening phase followed by randomization 
and a titration period in which extended-release metformin tablets or 
matching placebo (Glucophage XR, 500 mg/tablet [reduced mass]) will be 
titrated from 500 mg a day to 2000 mg a day in increments of 500 mg every 
10 days.  Enrolled study participants will undergo neuropsychological 
battery, clinical interviews, physical exam, and phlebotomy during four 
study visits at baseline, 6 months, 12-months, and 18-months.  Brain MRI, 
amyloid PET, and tau PET will be conducted in up to 186 participants after 
the baseline visit and after the 18-month assessment.  Adverse events and 
medication compliance will be checked every month.  The placebo group 
will undergo the same study assessments and procedures, receiving placebo 
tablets rather than metformin.   
Study Duration: 
Up to 8 years 
Participant Duration: 
The length of follow-up is 18 months. This could be extended by four 
months to allow for completion of procedures between randomization and 
start of investigational product (IP) and after the last follow-up visit. 
1.2 
SCHEMA 
Figure 1. The figure below represents a flow diagram of the study visits, from screening to the final visit. 
In addition to the visits described below, there will be monthly calls to assess safety and compliance. Visits 
1 to 4 may be divided into a remote component (questionnaires only) and an in-person component 
(phlebotomy, physical evaluations [vital signs, anthropometric measures, brief neurologic exam], 
neuropsychological testing), or conducted entirely in person, following the preference of the study 
participant. 
 
Telephone screen 
Total N 326:  Telephone Screen:  Screen potential participants by inclusion and exclusion criteria;  
 
 
 
Visit 
1: 
In-person 
screen/Baseline 
In-person Screen: Written informed consent, contact information, demographics, physical evaluations, EKG, 
phlebotomy, Neuropsychological battery, eligibility form. If eligible, complete baseline assessments including 
Neuropsychological Battery; Medical/Surgical/Psychological History; Current Medications, Cognitive Diagnosis; 
Physical Exam; Phlebotomy; Dispense IP; Brain MRI in cohort subset N=186). Amyloid and Tau PET scans in 
cohort subset (N=186). Study partners will answer questionnaires via telephone or in person.  
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1 Metformin 
N = 163  
Arm 2 Placebo 
N = 163  

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Titration 1 (day 10) 
 
Increase IP to 2 tablets; Safety and Compliance Assessment 
 
 
 
 
 
Titration 2 (day 20) 
 
Increase IP to 3 tablets; Safety and Compliance Assessment 
 
 
 
 
 
Titration 3 (day 30) 
 
Increase IP to 4 tablets; Safety and Compliance Assessment 
 
 
 
 
 
Visit 2: 6 months 
Neuropsychological Battery; Current Medications; Safety and Compliance Assessment; Dispense IP; 
Phlebotomy; Cognitive Diagnosis; Physical Evaluations; Study partners will answer questionnaires via telephone 
or in person. 
 
 
 
 
Visit 3: 12 months 
Neuropsychological Battery; Current Medications; Safety and Compliance Assessment; Dispense IP; 
Phlebotomy; Cognitive Diagnosis; Physical Evaluations; Study partners will answer questionnaires via telephone 
or in person. 
 
 
 
 
Visit 4: 18 months 
Neuropsychological Battery; Current Medications; Safety and Compliance Assessment; Dispense IP; 
Phlebotomy; Cognitive Diagnosis; Physical Evaluations; Study partners will answer questionnaires via telephone 
or in person. Brain MRI on cohort subset (N=186); Amyloid and Tau PET scans in cohort subset (N=186). 
 
 
 
 
 
1.3 
STUDY DURATION 
Recruitment is planned to end such that data collection in the phase II study in 326 participants can be 
completed by approximately April 30, 2026. Analyses and decision to proceed to a phase III trial would 
occur within 6 months of end of the phase II study. The Figure above shows the proposed schedule of 
assessments per participant. After telephone screening and preliminary determination of eligibility, 
participants will have an in-person screening visit. If they meet criteria for amnestic mild cognitive 
impairment (aMCI), the baseline visit will be completed. If blood tests do not show exclusion criteria, 
participants will be randomized, followed by a drug titration period. Metformin/placebo, referred to as 
Investigational Product (IP) from here on, will be titrated every 10 days by one tablet (500 mg), up to 2000 
mg a day. The neuropsychological battery, clinical interviews, physical exam, study partner interview, and 
phlebotomy, will be conducted at baseline and repeated every 6 months for 18 months, for a total of four 
visits. Brain imaging including brain MRI and amyloid and tau PET will be conducted in up to 186 
participants (186). Baseline brain imaging will be conducted after the baseline visit and after the 18 
months assessment. Medication compliance and adverse events will be checked every month via 
telephone call, text, or email, and in person during the scheduled in-person assessments every six months. 
2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
Our study focuses on late-onset (sporadic), not early onset (familial) Alzheimer’s Dementia. We refer to 
Alzheimer’s dementia as the clinical manifestation, and to Alzheimer’s disease (AD) as the underlying 
pathologic process throughout the application. Alzheimer’s dementia is the most common form of late 
onset dementia, accounting for 70% to 90% of cases in the U.S.1 Nearly half of persons 85 years and older 
have Alzheimer’s dementia,2 and the prevalence worldwide will quadruple by mid-century.3 The natural 
history leading to Alzheimer’s dementia starts slowly in late middle age with mild memory deficits, the 
clinical hallmark of Alzheimer’s dementia, progresses to amnestic Mild Cognitive Impairment (aMCI),4  and 

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progresses to dementia with continued decline in memory.5 Amnestic Mild Cognitive Impairment (aMCI) 
in considered a prevalent6 high risk group for AD4  and has become a target for secondary prevention for 
Alzheimer’s dementia, as we propose in MAP. Memory impairment of slow onset and progression is the 
primary clinical hallmark of aMCI and Alzheimer’s dementia.7 Thus, the primary outcome of MAP will be 
changes in verbal memory performance. The amyloid hypothesis,8 which posits that amyloid deposition 
in the brain is the key pathologic process underlying aMCI and Alzheimer’s dementia, has dominated the 
experimentation of therapeutic approaches for prevention and treatment. However, interventions that 
increase the clearance of amyloid9-11 or decrease its production12,13 among persons with Alzheimer’s 
dementia have thus far failed. These failures have led to clinical trials of anti-amyloid agents earlier in the 
natural history of Alzheimer’s disease, in asymptomatic persons and persons at risk without dementia, 
but has also led to the questioning of amyloid as a therapeutic target.14 An alternative approach for 
intervention is to target modifiable risk factors for Alzheimer’s dementia.15 Vascular risk factors (e.g. 
hypertension, dyslipidemia, type diabetes) have emerged as important predictors of Alzheimer’s 
dementia risk, and among them, type 2 diabetes and hyperinsulinemia have emerged as some of the most 
consistent and strongest risk factors in epidemiologic studies.16 We refer to type 2 diabetes as diabetes in 
the rest of this document.  
2.2 
BACKGROUND  
2.2.1 PERIPHERAL HYPERINSULINEMIA – INCREASED RISK OF ALZHEIMER’S  
Peripheral hyperinsulinemia is a plausible mechanism underlying the relation of diabetes with a higher 
risk of Alzheimer dementia. Diabetes is preceded and accompanied by insulin resistance causing 
hyperinsulinemia.17 Insulin resistance is caused by increased adiposity (e.g., overweight and obesity) in 
most affected individuals, and accompanied by other important risk factors including high inflammation, 
hypertension, and dyslipidemia, a cluster referred to as the metabolic syndrome.18 Hyperinsulinemia, 
diabetes, and the metabolic syndrome are known cerebrovascular risk factors.19 Thus, it seems reasonable 
to postulate that hyperinsulinemia and diabetes could increase Alzheimer’s dementia risk through 
cerebrovascular disease, a factor increasingly accepted to be important in the clinical manifestation of 
Alzheimer’s disease.20-23 However, peripheral hyperinsulinemia has also been demonstrated to result in 
lowering of insulin levels in the brain through decreased transport of insulin across the blood brain 
barrier,24 which in turn may lower the expression of insulin degrading enzyme (IDE),25 which is active in 
brain amyloid β (Aβ) clearance.25-28 Low brain insulin signaling is increasingly accepted to be a feature of 
Alzheimer’s disease pathology.29,30 This plausible mechanistic pathway is supported by findings in 
observational,31,32 brain imaging,33,34 autopsy,35 and experimental studies.36 In addition, peripheral 
hyperinsulinemia is related to other factors important in Alzheimer’s disease including increased 
inflammation,37 oxidation,38 and the accumulation of Advanced Glycation End Products (AGE).39 In 
summary, hyperinsulinemia could increase the risk of Alzheimer’s dementia through both cerebrovascular 
and Aβ related mechanisms,40 and this hypothesis has prompted testing strategies related to 
hyperinsulinemia and diabetes in the prevention and treatment of Alzheimer’s dementia.15 These 
strategies usually entail improving insulin sensitivity to lower insulin and glucose levels,41 an effective 
strategy for preventing diabetes that may be effective in decreasing the risk of Alzheimer’s dementia.15 
2.2.2 METFORMIN FOR ALZHEIMER’S PREVENTION 
We propose to repurpose metformin, a medication with proven efficacy in decreasing hyperinsulinemia 
and preventing diabetes, for the prevention of Alzheimer’s dementia. There are several proven diabetes 

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related pharmacological strategies that have been proposed for Alzheimer’s dementia treatment or 
prevention, including intranasal insulin, thiazolidinediones (a.k.a. PPAR-γ agonists),42 glucagon-like 
peptide agonists (GPA), and metformin.43 Intranasal insulin, used with the purpose of increasing brain 
insulin (without effect on peripheral insulin), showed preliminary evidence of a cognitive benefit in a pilot 
study in persons with mild Alzheimer’s dementia,44 and is now being tested in a larger trial. The glucagon-
like peptide agonists (GPA)45 both increase peripheral insulin secretion and sensitivity, are used in diabetes 
treatment, and have been hypothesized to be of benefit in Alzheimer’s dementia.46 The thiazolidinediones 
are powerful insulin sensitizers effective in lowering insulin resistance47 and preventing diabetes,42 with 
efficacy similar to lifestyle strategies (diet and exercise that lead to weight loss) and greater than 
metformin.48 However, thiazolidinediones have concerning side effects including edema, congestive heart 
failure (CHF), and in the case of rosiglitazone, myocardial infarction (MI) and stroke,49 which led to a black 
box warning from the Food and Drug Administration (FDA).50 Rosiglitazone was tested for secondary 
prevention of cognitive decline in mild Alzheimer’s dementia among persons without diabetes and was 
found to be non-efficacious in a randomized trial in 511 subjects51 after promising results in a pilot study.52 
However, there was evidence of benefit among non-carriers of APOE-ε4, similar to our pilot study (see 
2.2.4). The thiazolidinedione pioglitazone seems to have a lower risk of MI and stroke compared with 
rosiglitazone, but shares class side effects such CHF.53 A randomized placebo controlled trial of 
pioglitazone in 3,500 subjects at risk for aMCI (NCT01931566; Biomarker Qualification of Mild Cognitive 
Impairment Due to Alzheimer’s Disease and Safety and Efficacy Evaluation of Pioglitazone in Delaying its 
Onset [TOMMORROW]) was recently stopped after an interim futility analysis.54 It could be speculated 
that the adverse vascular effects of the thiazolidinediones 50 may have eclipsed the potential beneficial 
effects for Alzheimer’s dementia related to the increase in peripheral insulin sensitivity and lowering of 
insulin and glucose levels.55 Even if found efficacious, use of thiazolidinediones for Alzheimer’s dementia 
prevention could be limited due to their adverse effects risk profile. Metformin is a medication belonging 
to the biguanide class.56,57 It treats and prevents diabetes by suppression of hepatic glucose output, 
increasing insulin mediated glucose disposal, by increased intestinal glucose use, and by decreasing fatty 
acid oxidation; 58 these effects are accompanied by reduced pancreatic insulin secretion and lower insulin 
levels in blood in response to glucose loads. While the mechanisms for the action of metformin are not 
completely understood, it clearly reduces insulin levels,41 inflammation and thrombosis,59 and the risk of 
the metabolic syndrome60 and diabetes61 in persons at risk for diabetes. Metformin is usually the first step 
in pharmacological treatment of diabetes,62 but it is increasingly used in persons without diabetes for 
diabetes prevention based on the findings of the Diabetes Prevention Program (DPP).61 In the DPP, 
metformin was more effective than lifestyle (diet and exercise) intervention in preventing diabetes after 
10 years.63 The only common side effect of metformin in clinical trials has been gastrointestinal 
intolerance, occurring in 10% of subjects. In the DPP, the rate of serious adverse events for metformin 
was the same as for placebo. Metformin seems to be the most realistic and safe long-term strategy to 
reduce insulin levels and prevent diabetes when compared to lifestyle intervention63 and 
thiazolidinediones,49 because of its effectiveness and low risk of adverse events. Cerebrospinal fluid levels 
of metformin are approximately 10% of the plasma levels,64 indicating some crossing of the blood brain 
barrier, but we postulate that it acts on the Alzheimer’s disease process through reduction of peripheral 
insulin levels that affect brain clearance of Aβ. 25,65,66In addition, Metformin also decreases AGE,67,68 
inflammation,59 coagulation,59 and prevents the metabolic syndrome (diabetes, hypertension, obesity, 
dyslipidemia),60 factors that may also influence Alzheimer’s dementia risk through cerebrovascular or 
neurodegenerative mechanisms.55 The beneficial pleomorphic, metabolic, anti-inflammatory, and anti-
thrombotic effects of metformin have led to the hypothesis that metformin is a wonder drug that may be 
effective in cancer prevention and treatment69 as well as for the prevention of the adverse effects of 
aging.70 Thus, we propose metformin as the ideal diabetes drug to repurpose for prevention of Alzheimer’s 
dementia in persons at risk. This premise is further supported by our preliminary data. The most common 

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side effect of metformin in gastrointestinal intolerance (10%), which is significantly decreased with the 
extended-release form that we propose in MAP.71 The most serious side effect, lactic acidosis, is very rare 
(< 0.01%),72 and avoided by precluding its use in person with contraindications, as we will do in MAP. More 
recently, there is recognition that metformin might cause malabsorption of vitamin B12 (cobalamin),73 
which could impact cognition.74 However, this side effect is very rare, and we will monitor B12 levels at all 
study visits in MAP. 
2.2.3 OVERALL SUPPORTING EVIDENCE 
There are conflicting data relating metformin with Alzheimer’s dementia risk, but the best evidence favors 
the benefits of metformin on Alzheimer’s dementia risk. Several laboratory and human studies have 
suggested that metformin increases the risk of Alzheimer’s dementia, but this is countered by other 
studies indicating that it is beneficial. One study in a neuronal cell culture model reported that metformin 
increases the biogenesis of amyloid peptides via up-regulation of BACE1 Transcription.75 Another study in 
a mouse model of Alzheimer’s disease reported that metformin facilitates amyloid beta generation by 
beta and gamma secretases via autophagy activation.76 These seemingly deleterious effects of metformin 
on Alzheimer’s disease risk are countered by studies that have found that metformin activation of AMPK-
dependent pathways is neuroprotective in human neural stem cells against amyloid beta induced 
mitochondrial dysfunction,77 and that metformin attenuates cognitive impairments in hypoxia-ischemia 
neonatal rats by improving remyelination.78 A recent study found that metformin prevented amyloid 
accumulation and memory impairment in Alzheimer’s (APP/PS1) mice.79 Studies in humans are conflictive 
as well. One case control study in an administrative dataset concluded that metformin was associated 
with an increased risk of dementia, but this association was not apparent in crude analyses, appeared 
after adjustment for demographics, and was seen for 10-29 metformin prescriptions and 60 and more 
metformin prescriptions (compared to no-prescriptions), but was null for 1-9 or 30 to 59 prescriptions.80 
In another cross-sectional study sampled by cognitive status (normal, mild cognitive impairment, 
dementia) metformin was reported to be associated with a higher risk of cognitive impairment.81 The 
designs of these two studies were possibly subject to selection bias and confounding by indication, that 
is, that persons who had dementia and diabetes were more likely to be taking metformin; this is not 
surprising because elderly subjects with diabetes and dementia are switched from oral agents that can 
cause hypoglycemia (sulfonylureas) to those that do not cause hypoglycemia (e.g., metformin), in order 
to prevent this dangerous complication. Other studies with better designs have shown that metformin is 
not associated with a higher risk of cognitive impairment, and in fact, may be associated with a lower risk. 
In the Diabetes Prevention Program Outcomes Study (DPPOS), among persons with diabetes or pre-
diabetes, longitudinal cumulative exposure to metformin was not associated with cognitive performance, 
and metformin showed a non-significant trend towards a benefit in memory performance in a second 
wave of cognitive testing.82 The results of the third wave of cognitive testing in DPPOS are pending.  The 
best epidemiologic study to date was carried out in a cohort of over 28,000 United States’ veterans 65 
years and older,83 which reported that that the risk of dementia was significantly lower among those with 
diabetes taking metformin (which lowers insulin levels) compared with those taking sulfonylurea (which 
increases insulin levels). Compared to other studies this was a cohort study that used propensity scores 
to account for confounding by indication that is common in pharmacoepidemiologic studies.84,85  A recent 
pilot placebo-controlled randomized cross-over study in 22 persons with MCI or mild Alzheimer’s 
dementia64 showed that metformin was associated with improved executive functioning, and trends 
suggesting improvement in learning, memory, and attention. Our preliminary data in humans (see B.1.5.1) 
and animals (see B.1.5.2) support the beneficial effects of metformin on Alzheimer’s dementia risk. 
2.2.4 BIOMARKERS OF ALZHEIMER’S DISEASE 

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Increased understanding of AD neuropathology and its natural history has enabled the development of 
brain imaging and cerebrospinal fluid AD biomarkers for the diagnosis and detection of dementia that can 
be used in clinical trials. Decades of advances in AD research, particularly in cerebrospinal fluid (CSF) and 
brain imaging biomarkers,86,87 have led to the dominance of 3 neuropathological constructs: brain 
amyloid, brain tau, and neurodegeneration. Current understanding of the natural history leading to 
dementia due to AD can be summarized as follows:86 the 2 main proteinopathies underlying AD, amyloid 
and tau, are separate processes, but amyloid deposition accelerates tau deposition; amyloid and tau 
deposition precede and cause neurodegeneration, which leads to the clinical syndromes of aMCI and 
dementia. The measurement of amyloid, tau, and neurodegeneration features prominently in the 
NIA/Alzheimer’s Association (AA) 2018 research framework.88 This framework proposes to conduct 
research in which individuals are classified by the presence or absence of evidence of amyloid, tau, and 
neurodegeneration (A/T/N), with or without clinical manifestations, for the purpose of better 
understanding the mechanisms and sequence of neuropathology. The 2018 research framework has been 
enabled by the widespread availability of accurate CSF and brain imaging markers of amyloid, tau, and 
neurodegeneration. As compared with cognitively normal individuals, persons with AD dementia show 
lower CSF Aβ4289 and higher brain amyloid burden on amyloid PET,90 higher CSF T-tau and P-tau89 and 
higher brain tau burden on tau PET,91 and lower cortical thickness and brain volumes on MRI.92 More 
recently, neurofilament light (NFL) in CSF has also been reported to define neurodegeneration.89 We do 
not propose to do lumbar puncture in MAP because, in our experience, it is perceived as invasive by study 
participants, and it risks recruitment and retention. We propose to conduct amyloid and tau PET in MAP 
participants undergoing MRI because we have good experience in terms of participant acceptability. PET 
also has the added advantage of providing information on brain regional distribution of amyloid and tau.  
2.2.5 PLASMA BIOMARKERS OF ALZHEIMER’S DISEASE 
Blood-based biomarkers of AD have lagged behind brain imaging and CSF biomarkers, but recent 
developments are enabling the use of blood-based biomarkers in AD research. The blood-brain barrier is 
altered in aging and AD.93 The increased permeability between the brain and the periphery makes it 
possible for blood-based biomarkers to be representative of pre-clinical changes in AD.94 Extant proteomic 
methods to measure blood-based biomarkers for AD include mass spectrometry, immunocapture, and 
aptamer-based techniques. However, issues around lower limit of detection, depletion of lower molecular 
weight proteins, and antibody availability have limited the use of these methods in particular.95 More 
recently, ultrasensitive immunoassays coupled with mass spectrometry show greater promise.96 The 
commercially available single-molecule array (Simoa) is a novel method to measure Aβ40, Aβ42, tau 
and neurofilament light (NFL) in plasma,97 which we propose to use. Below we provide a brief review of 
the literature for each plasma biomarker. 
Plasma Aβ. Using Simoa technology in 248 participants with subjective cognitive decline from the 
SCIENCe project and Amsterdam Dementia Cohort, plasma Aβ42/Aβ40 ratio and plasma Aβ42, but not 
plasma total tau, identified abnormal CSF-amyloid status suggesting that plasma Aβ42/Aβ40 has the 
potential to be used as a screening measure to identify AD related neuropathological changes in 
cognitively normal individuals with subjective cognitive decline.98 Our consultant to this project, Henrik 
Zetterberg, is an active collaborator in the Swedish BioFINDER study. In this cohort study, plasma Aβ42 
and Aβ40 ascertained with Elecsys immunoassays (Roche Diagnostics) predicted Aβ status, as defined 
from cerebrospinal fluid Aβ42/Aβ40 ratio, with an area under the receiver operating curve (AUC)=0.80. 
This was found to be independent of age, ApoE, or cognitive status.99 Plasma Aβ42/Aβ40, measured with 
Simoa, was also predictive of cerebral amyloidosis in a sample of 276 cognitively intact individuals with 

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subjective memory complaints from the INSIGHT-preAD study, a French academic university-based cohort 
that is part of the Alzheimer Precision Medicine Initiative Cohort Program.100  
Plasma tau. Plasma tau ascertained using the Simoa assay has been weakly or not correlated with CSF 
tau levels in both the BioFINDER study and Mayo Clinic Study of Aging.101 However, in a sample of patients 
with AD, MCI and cognitively healthy controls from the ADNI, higher levels of Simoa-based plasma tau 
were observed in AD dementia compared to both aMCI patients and cognitively healthy controls.102 More 
recent data from the Framingham Heart Study examined the use of plasma total tau, measured with 
Simoa, as a blood biomarker for dementia and related endophenotypes. In a sample of 1,453 
participants, a 1 standard deviation (SD) increase in the log of plasma total tau level was associated with 
a 35% increase in AD dementia risk. Higher plasma total tau was also associated with poorer cognition, 
and smaller hippocampi and more neurofibrillary tangles and microinfarcts at autopsy.103 An additional 
study also reported a significant correlation of plasma phosphorylated tau and total tau with brain tau 
deposition by PET imaging.104  
Plasma NFL. Simoa based plasma NFL correlations with CSF levels are high105 and additional reports from 
ADNI suggest that plasma NFL had high diagnostic accuracy for identifying patients with dementia vs. 
controls (AUC=0.87).106 A recent study of 1,583 participants from ADNI reported the association between 
clinical diagnoses, CSF biomarkers, imaging measures and cognition with longitudinal Simoa-based 
plasma NFL levels.107 Levels of plasma NFL increased over 11 years in patients with MCI and AD dementia. 
The authors also reported that a longitudinal increase in plasma NFL correlated with CSF biomarkers (e.g., 
lower Aβ42, high total tau, high phosphorylated tau, and higher levels of neurodegeneration detected 
from MRI) and poorer cognitive performance. Our preliminary data in 34 participants shows that persons 
with dementia have appreciably higher levels of plasma NFL and tau compared with persons with normal 
cognition, with less appreciable differences for Aβ42/Aβ40 ratio. The fact that our pilot data agree with 
some of the recent literature for NFL and tau supports our proposal.  
The field of AD plasma biomarkers is rapidly advancing,108 and the biomarkers mentioned above may 
become obsolete or be replaced by better ones by the time that these biomarkers are measured, after 
the end of data collection. For example, p-tau 217 has emerged as the best plasma biomarker of amyloid 
burden. 109 Neuroinflammation can now be assessed in plasma with glial fibrillary acidic protein (GFAP).110 
Plasma measures of synaptic integrity and other neuropathologies are being developed 111 that could be 
validated by the time we measure plasma biomarkers. Given these ongoing advances in plasma AD 
biomarkers, we refer broadly to AD plasma biomarkers in this protocol.  
2.2.6 COVID-19 AND COGNITION 
Reports of the impact of COVID-19 on cognition and long-term cognitive sequelae are increasing, 112,113 
but the cognitive impact of COVID-19 on cognition is not yet understood. Given that we are recruiting a 
sample that is at risk of both cognitive impairment and COVID, we added a questionnaire to explore 
COVID-19 history as a covariate and potential modifier of the effectiveness of metformin.  
2.2.7 PRELIMINARY DATA 
2.2.7.1. MAP is based on the results of the Phase II trial of metformin in aMCI (MetMCI). MetMCI 
(NCT00620191) was funded by the National Institute on Aging (NIA; AG026413; PI; Luchsinger; 05/2008-
04/2013) and the Alzheimer’s disease Drug Discovery Foundation (ADDF; # 270901; PI: Luchsinger; 
12/2007-11/2011). MetMCI was a single-site, double-blind placebo-controlled 1:1 randomized pilot trial 
of short acting metformin 1000 mg (two 500 mg tablets) twice a day for 12 months in subjects with late 

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aMCI, defined by the Petersen criteria.114 Randomization was stratified by the presence or absence of 
APOE-ε4 genotype, based on previous studies demonstrating a higher risk of dementia among persons 
with hyperinsulinemia who are heterozygous or homozygous for APOE-ε4,31,32 and the results of a clinical 
trial of rosiglitazone showing cognitive benefits among persons without an APOE-ε4 allele.51 Participants 
were seen once a week in the first 4 weeks of the study during metformin titration and were then 
evaluated at months 3, 6, 9, and 12. Half the sample (40 participants) were invited to participate in a brain 
imaging sub-study. Participants were 80 subjects aged 55 to 90 years with aMCI without treated diabetes, 
and with a body mass index (BMI) of 25 kg/m2 or higher (overweight or obese by National Heart, Lung, 
and Blood Institute (NHLBI)) criteria115). Screening was conducted following a 2-step process. First, 
participants who were interested in participating were screened by telephone for demographic and 
medical inclusion and exclusion criteria. The Telephone Interview for Cognitive Status (TICS)116 was 
administered to screen out persons who were unlikely to have any memory impairment. A TICS Score > 
34 out of 41 was considered normal cognition. Persons with this score were not invited to participate. 
Persons who passed the telephone screen were invited for an in-person screening that included a physical 
exam, blood tests, and a neuropsychological battery. Participants were randomized to metformin or 
identical matching placebo, both provided by Merck-Lipha of France. The maximum dose of metformin 
was 1000 mg twice a day, as is commonly used in clinical practice. Metformin was as 500 mg tablets. 
Metformin was titrated weekly from 500 mg once a day to 1000 mg twice a day over 4 weeks. Subjects 
were maintained on the highest tolerated dose. Participants who did not tolerate the study drug were 
invited to continue in the study and were included in the ITT analyses. Metformin and placebo were 
supplied every 3 months, when participants were asked for side effects and contraindications to 
metformin in addition to undergoing safety laboratory tests. The primary outcomes of the study were 
changes from baseline to month 12 in total recall of the Buschke SRT117 and the Alzheimer’s Disease 
Assessment Scale-cognitive subscale (ADAS-cog).118 The primary imaging outcome was changes from 
baseline to month 12 in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus measured 
by non-quantitative brain [18] F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) PET with magnetic resonance 
imaging (MRI) co-registration. We conducted a washout period of 2 weeks119 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. Analysis of Covariance (ANCOVA) was used to compare outcomes between the treatment 
groups following an ITT approach adjusting for variables that were different at baseline if necessary. 
Imputation with last-observation-carried-forward (LOCF) was used to account for missing follow-up data. 
The most successful outreach strategy was newspaper ads, which was the source of 84% of all contacts. 
Sixty-five 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. At 12 months, study completion was similar in the 2 arms 
(33 persons completed the placebo arm and 32 the metformin arm; p = 0.99). Based on this experience, 
we are proposing for MAP an in-person screen to recruitment ratio of 3, since MAP will include both early 
and late MCI. We also propose to use ads again as an effective strategy for recruitment.  
Table 1. Comparison of baseline variables in the 
MetMCI study.  
Metformin 
(n=40) 
Placebo 
(n=40) 
p 
Age in years (SD) 
65.3 (7.0) 
64.1 (7.9) 
0.49 
Women (%) 
18 (45) 
24 (60) 
0.21 
Education in years (SD) 
13.8 (3.4) 
13.1 (4.5) 
0.44 
Ethnic group (%) 
       Hispanic  
       Non-Hispanic Black 
       Non-Hispanic White 
 
0.46 
 17 (42.5) 
13 (32.5) 
 
11 (27.5) 
15 (37.5) 
12 (30.0) 
12 (30.0) 
Apolipoprotein E ε4 (%) 
10 (25.0) 
11 (27.5) 
0.79 
Body Mass Index in kg/m2 (SD) 
30.9 (4.1) 
31.3 (4.7) 
0.65 

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Results: The only statistically significant difference between the groups at baseline (Table 1) was the 
ADAS-Cog score, which was lower (better) in the metformin group. 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). 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. 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). High sensitivity C-reactive protein (hs-CRP), a measure of inflammation and vascular 
risk,120 and a correlate of memory impairment in our center121 decreased in the metformin group and 
increased in the placebo group (-0.3 vs. 1.0 mg/dL; p = 0.07). 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 significant (p = 0.63). Table 2 below shows the comparison in the primary clinical outcomes of 
the study, changes from baseline to month 12 in the ADAS-Cog score, and the total recall of the Selective 
Reminding Test (SRT).  
Table 1. Comparison of baseline variables in the 
MetMCI study.  
Metformin 
(n=40) 
Placebo 
(n=40) 
p 
Systolic Blood Pressure in mmHg (SD) 
130.8 (10.9) 
132.1 (12.4) 
0.62 
Total Cholesterol in mg/dl (SD) 
204.2 (43.6) 
208.2 (46.7) 
0.71 
High Density lipoprotein in mg/dl (SD) 
51.5 (14.1) 
58.3 (17.7) 
0.06 
Hemoglobin A1C in % (SD) 
6.1 (0.8) 
6.1 (0.5) 
0.92 
Hemoglobin A1C > 6.5% (%) 
7 (17.5) 
6 (15.0) 
0.76 
High Sensitivity C-reactive protein in mg/dl (SD) 
2.9 (3.6) 
3.7 (2.9) 
0.32 
Insulin in IU/dl (SD) 
16.3 (9.5) 
13.4 (7.6) 
0.20 
ADAS-Cog Score (SD) 
12.0 (4.0) 
14.6 (6.1) 
0.02 
Selective Reminding Test Total Recall (SD) 
34.2 (7.9) 
36.1 (9.5) 
0.32 

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Table 2. Comparison of changes from baseline to 12 
months in the ADAS-cog and total recall of the SRT 
between metformin and placebo. Crude (unadjusted) 
analyses are from T-tests. Adjusted analyses are from 
Analyses of Covariance adjusted for was the baseline 
score of the ADAS-cog. 
 
Metformin 
Placebo 
p 
ADAS-Cog 
Baseline  
12.0 ± 4.0 
14.6 ± 6.1 
0.02 
Last visit 
12.1 ± 3.8 
12.8 ± 6.2 
0.52 
Crude difference 
0.0 ± 3.3 
-1.98 ± 5.5 
0.06 
Adjusted difference 
-0.5 ± 4.1 
-1.4 ± 4.1 
0.34 
Total recall SRT 
Baseline  
34.2 ± 7.9 
36.1 ± 9.5 
0.32 
Last visit 
43.6 ± 9.1 
41.5 ± 8.4 
0.31 
Crude difference 
9.4 ± 8.5 
5.7 ± 8.7 
0.05 
Adjusted difference  
9.5 ± 6.1 
5.4 ± 6.1 
0.05 
Both the SRT and ADAS-Cog scores 
improved in the placebo and metformin 
groups (increases in SRT total recall, 
decreases in ADAS-COG scores). Crude 
analyses showed a greater improvement in 
the SRT in the metformin group, but the 
difference for the ADAS-Cog favored the 
placebo group. However, 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) and the difference for the ADAS-Cog 
was attenuated and not significant.  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). 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). 
There were no differences between metformin and placebo in changes in digit span backwards, the 
neuropsychiatric inventory, the mini-mental status exam (MMSE), paragraph recall, or ADCS Clinical 
Global Impression of Change for Mild Cognitive Impairment (CGIC-MCI).122 One person in the placebo 
group and none in the metformin group converted to dementia. We conducted linear regression models 
examining the relation of the metformin dose with the primary outcomes, changes in total recall of the 
SRT and the total score of the ADAS-cog. 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. There was no 
association between the highest metformin dose and changes in the ADAS-Cog (0.7 ± 4.8; p = 0.56). Based 
on these findings, we are proposing to change the metformin formulation to the better tolerated 
extended-release form (Glucophage XR [reduced mass]), and to exclude participants who cannot tolerate 
at least 1000 mg of metformin a day, an approach adopted by the clinical trials of diabetes using 
metformin.123 

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Post-hoc subgroup analyses. We 
conducted 
post-hoc 
subgroups 
analyses: metformin showed better 
performance compared with placebo 
in younger persons, those without 
APOE-ε4, those with lower HbA1c, 
and those with higher insulin levels. 
There were no differences in sex 
strata.  There were no differences for 
the ADAS-Cog in any of the strata. 
Based on these findings, and previous 
evidence of effect modification by 
APOE-ε4,51 we  will pay particular 
attention to APOE-ε4 in our decision 
to proceed to phase III. The results for 
younger persons and those with 
higher insulin levels are not surprising 
because metformin is known to be 
more effective in younger persons 
and in those with higher insulin 
resistance. The results for HbA1c may 
suggest that metformin is most 
effective while persons are insulin 
resistant 
with 
hyperinsulinemia, 
before 
pancreatic 
failure 
and 
increases in glucose. These subgroups 
findings should be interpreted with 
caution given the small strata, and we 
will explore these modifiers in 
exploratory analyses in MAP. 
Table 3. Subgroup analyses 
 
Metformin 
Placebo 
Total Recall Selective Reminding Test 
 
N 
Mean + SD 
N 
Mean + SD 
P  
Age group 
≤ 63.7 years 
18 
12.2 ± 7.5 
22 
6.3 ± 7.5 
0.02 
> 63.7 years 
22 
6.9 ± 9.8 
18 
5.4 ± 6.7 
0.67 
APOE-ε4  
Negative 
30 
10.7 ± 8.2 
29 
5.9 ± 8.6 
0.04  
Positive 
10 
5.7 ± 9.1 
11 
5.2 ± 9.2 
0.89 
Body Mass Index 
< 30 kg/m2 
21 
9.0 ± 10.0 
19 
3.9 ± 10.0 
0.13 
≥ 30 kg/m2 
19 
10.3 ± 6.9 
21 
6.9 ± 6.8 
0.14 
HbA1c  
≤ 6.0 % 
23 
12.2 ± 7.1 
20 
6.6 ± 7.1 
0.01 
> 6.0 % 
17 
6.3 ± 9.0 
20 
4.0 ± 9.8 
0.49 
Insulin  
≤ 9 IU/dl 
21 
6.7 ± 8.7 
19 
4.4 ± 8.7 
0.42 
> 9 IU/dl 
19 
12.4 ± 7.8 
21 
6.8 ± 8.0 
0.03 
ADAS-Cog 
Age group 
≤ 63.7 years 
18 
- 0.2 ± 3.5 
22 
-1.2 ± 3.5 
0.38 
> 63.7 years 
22 
-0.5 ± 5.2  
18 
- 1.8 ± 6.3 
0.50 
APOE-ε4  
Negative 
30 
   0.1 ± 3.8  
29 
-1.2 ± 4.1 
0.24 
Positive 
10 
-2.3 ± 4.4 
11 
-2.2 ± 4.4 
0.97 
BMI 
< 30 kg/m2 
21 
-0.8 ± 6.1 
19 
-2.2 ± 6.5 
0.56 
≥ 30 kg/m2 
19 
-0.2 ± 3.7 
21 
-0.7 ± 3.6  
0.72 
HbA1c > 6.0% 
≤ 6.0 % 
23 
0.3 ± 3.9  
20 
 -0.1 ± 3.9  
0.66 
> 6.0 % 
17 
-1.8 ± 4.4  
20 
-2.8 ± 4.3 
0.51  
Insulin  
≤ 9 IU/dl 
21 
-0.51 ± 4.5 
19 
-0.4 ± 4.4 
0.93 
> 9 IU/dl 
19 
-0.5 ± 3.9  
21 
-2.4 ± 3.9  
0.15 
Brain imaging outcomes: 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). 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). Secondary 
regions of interest (ROI) 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. 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). Although this difference 
was not statistically significant, it supported the beneficial findings for metformin (lowering of Plasma Aβ-
42 is related to higher AD risk124). Post hoc MRI analyses. MRI parameters were not pre-specified 
outcomes in MetMCI. MRI was only used for FDG PET co-registration, and ROI were manually drawn. In 
collaboration with Adam Brickman, PhD, we processed the MRI data using FreeSurfer and obtained data 
brain volumes, with particular attention to hippocampal and entorhinal cortex volumes and thickness 
because they have been recommended for the longitudinal assessment of neurodegeneration and 
Alzheimer’s disease severity..125 Total (left + right) Hippocampal volume decreased less in the metformin 
group (-47.16 mm3) as compared with the placebo group (-140.5 mm3) but this difference was not 
statistically significant (p = 0.11). These appreciable differences remained after adjusting for age, sex, and 

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APOE-ε4. There were no differences for entorhinal cortical thickness (p = 0.51). Given these findings, we 
selected hippocampal volume as our outcome measure of neurodegeneration. 
Post-hoc FDG PET analyses. We conducted post-hoc voxel-based analyses instead of the original ROI based 
analyses seeking additional evidence that supported metformin for AD prevention. rT1 MRIs were 
anatomically segmented with FreeSurfer and were linearly registered (MATLAB 2017a, SPM12) to the 
summed PET data in native PET space. The PET data was intensity normalized to the global mean and then 
each voxel was divided by the average in superior cerebellum (FreeSurfer defined mask) to create 
parametric standard uptake value ratio (SUVR) images.126 The T1 MRI was spatially normalized 
(MAT2017a, SPM12) to the T1 template in MNI space, and the non-linear transformation matrix was 
applied to the SUVR image. SUVR images were spatially smoothed with an isotropic 8mm Gaussian kernel 
for voxel-wise analysis A voxel-wise 2x2 ANOVA was used to test for differences in FDG SUVR by treatment 
and by time point (MATLAB 2017a, SPM12). Statistical significance was defined at p<0.001, uncorrected 
for multiple comparisons, with no cluster size threshold. Descriptively, the metformin group had lower 
FDG SUVR compared to the placebo group at baseline (main effect of treatment), the baseline scan had 
higher FDG SUVR compared to the follow-up scan (main effect of time point), and the decrease in FDG 
SUVR from baseline to follow-up was greater in the placebo group compared to the metformin group 
(interaction between treatment and time point; Figure 2 below). Interestingly, the metformin group did 
not show decreases in posterior brain, but the placebo group did, suggesting that metformin could reduce 
FDG hypometabolism. In aggregate, these results for FDG-PET support the beneficial results of metformin 
found for the clinical outcomes.  
2.2.7.2. Metformin improves cognition and memory deficits found in diabetic (db/db) mice.  The PI has 
been conducting experiments examining cognition in diabetic mice and the effect of metformin on 
cognition, as part of grant RF1AG051556 (PI: Brickman, Luchsinger, Moreno), in collaboration with 
Herman Moreno at SUNY Downstate. We assessed cognitive and memory deficits using Active Place 
Avoidance (APA)127 in db/db mice who were 10 months old, (n=18, 50% male) and 16 Heterozygous 
(db/wild type) mice (50% male) as controls. There was a significant difference between the groups in both 
APA (RM ANOVA F = 7, 21, p = 0.011) and APA conflict (RM ANOVA F = 5, 21 p = 0.021), indicating cognitive 
deficits in diabetic mice compared with controls. GLM repeated measures analysis demonstrated a 
significant sex effect in APA but not in APA conflict, with more abnormalities observed in female mice. 
The deficit in APA of old mice suggest that old female diabetic mice have deficits in hippocampal 
dependent spatial learning. The deficit in males and females observed in APA conflict suggests that db/db 
mice have deficits in set-shifting, a deficit that frequently occurs in Alzheimer’s dementia.128   

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2.2.7.3. MAP was prepared with a comprehensive consultation with the Trials Innovation Center (TIC) 
at Johns Hopkins University, one of the three hubs of the NCATS trial innovation network (TIN).  In 
December of 2016 we applied for a consultation with the TIC at JHU-Tufts proposing to conduct a phase 
III trial of metformin in aMCI. The changes in design from the MetMCI study to the current proposal 
prompted the recommendation to conduct a phase II/III study instead of a phase III study.129 The 
observation that a minority of participants achieved the maximum dose in the pilot study led us to propose 
the use of the better tolerated extended release metformin. The observation that there were significant 
practice effects for both outcomes led us to do repeated testing in the titration period in order to establish 
a cognitive baseline at the end of titration. The increasing acceptance of early MCI as part of the 
continuum of prodromal AD130,131 led us to extend the study sample to include both early and late MCI. 
Our finding that the SRT was the outcome that showed a signal led us to choose a related outcome that 
is more sensitive to early change, the FC-SRT. Given these changes in the design we propose a larger phase 
II study with an a-priori rule to advance to phase III, instead of directly proposing a phase III study. The 
advantage of this design is that a phase II/III trial is an adaptive approach that decreases the time, number 
of participants, and cost needed to make a decision about the efficacy of a treatment.129 Although there 
will participant enrollment will be suspended while the data of the phase II portion is analyzed to make a 
decision to move to phase III, the design and outcomes of the phase III study will be similar to phase II, 
allowing inclusion of the phase II participants as part of the analytic sample for the final phase III study.129 
As part of the TIC consultation, we shared our MetMCI dataset with the statistical team at JHU-Tufts, who 
replicated our findings and analyzed all data points (the primary MetMCI analysis only compared changes 
between baseline and 12 months between study arms, using LOCF for missing 12 month data). The 
differences in all time points for the SRT can be seen in Table 4 (below). The metformin arm had lower 
total recall at baseline compared with placebo but went on to have better performance at months 3, 6, 
and 12 compared with placebo, and similar performance at month 9. Both study arms showed 
improvements in recall, but the improvement was strongest in the metformin group. In order to 
determine the sample size of for the phase II/III study at the time of the original grant application, the TIC 
team used the MetMCI data to estimate the initial sample size for MAP (n=370, 185 per arm). The 
approach to the sample size calculation is detailed in section 4.4 (statistical design and power). The 
 
Figure 2. The parameter estimates and statistically 
significant clusters from the 2x2 ANOVA. Parameter 
estimates are all shown in positive direction (e.g., Placebo 
minus Metformin, Baseline minus Follow-up, Difference in 
Baseline and Follow-up for Placebo minus that for Metformin) 
Comparison of 10 months old db/db mice 
treated with 0.1% metformin diet for 2 
months with 10 months old heterozygous 
mice demonstrated that the differences 
seen before in APA or APA conflict were not 
observed, 
indicating 
that 
metformin 
reversed the cognitive deficits observed in 
db/db mice compared with the control 
mice (RM ANOVA F = 1,2; p = 0.21; F = 2, 1; 
p = 0.11 respectively).  A significant 
difference was observed in db/db mice 
treated with metformin vs. control db/db 
without treatment in both APA and APA 
conflict (F = 5, 21; p = 0.021; F = 4.11; p = 
0.02). These data strongly suggest that 
metformin provided chronically improves 
the cognitive deficits observed in old 
diabetic mice and lends further justification 
for the conduct of MAP.  

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consultation with the TIC also included a consultation for recruitment and retention strategies with the 
NCATS Recruitment Innovation Center (RIC) at Vanderbilt University. The RIC assisted the PI in choosing 
sites according to their capacity to recruit, their previous experience in Alzheimer’s disease clinical trials, 
and their affiliation with a local Clinical Translational Science Award funded by NCATS. 
 
 
 
 
Table 4. Comparison of the SRT at all time points between metformin and placebo in MetMCI 
2.2.7.3.1. Design changes in Protocol version 1.9 based on MetMCI data. The assumptions used for the 
original study design were reconsidered for protocol version 1.9 based on the MetMCI data, resulting in 
the following changes: (1) The sample size was reduced to 326 from 370; (2) the follow-up time was 
reduced to 18 months from 24 months. The rationale for the reduction in sample size is found in section 
4.4. The rationale for reducing the study follow-up is that the great majority of recent and ongoing clinical 
trials of MCI and early AD have a follow-up period of 18 months. In addition, the effect in MetMCI was 
observed at 12 months, thus requiring only an additional 6 months to observe if the effect persists. 
2.2.7.4. Middle aged persons diabetes treated with metformin have lower amyloid SUVR than persons 
with pre-diabetes. We compared amyloid levels (positive, intermediate, low) between persons taking and 
not taking metformin in a cohort of 266 persons aged 64 years of age from an ongoing study of AD 
biomarkers in Northern Manhattan. Brain Aβ was measured with 18F-florbetaben PET. We examined the 
association of metformin use with Aβ levels using ordinal logistic regression. Persons who reported 
metformin use had lower levels of Aβ (Odds ratio [OR] = 0.48; 95 confidence interval [CI] = 0.24, 0.97) 
after adjustment for age, sex, and APOE-ε4, and diabetes status. This association remained evident after 
excluding persons with normal glucose tolerance (NGT; OR = 0.35; 95 % CI = 0.16, 0.75), and excluding 
both persons with pre-diabetes and NGT (OR = 0.44; 95% CI = 0.16, 1.22). These results come from a cross-
sectional analysis, which limits the inferences that can be made. However, they suggest that metformin 
use may be associated with lower brain Aβ. 
2.2.7.5.  We conducted a pilot study of Simoa plasma NFL, tau, and Aβ40, Aβ42 in a study of dementia 
detection among persons with cognitive concerns that shows that NFL and tau are promising plasma 
biomarkers. We tested plasma biomarkers in an ongoing study of dementia detection in primary care 
(AG057898; PI: Devanand, Luchsinger). Consultant Zetterberg advised us to use the Simoa platform with 
the company Quanterix (Lexington, MA, USA), with whom they have worked in the development of 
ultrasensitive AD fluid biomarkers.96 Thus, we conducted a pilot study of these plasma biomarkers in a 
subsample (n=34) of participants, using frozen plasma. The rationale of the sample size of 34 was that this 
is the number of duplicate samples that can be tested in a single Simoa multiplex plate. A multiplex 
immunoassay kit was used for the quantification of total tau, Aβ40, and Aβ42 in plasma. Plasma NFL was 
measured with a single immunoassay. Table 5 below shows the mean (SD) of the plasma AD biomarker 
levels by cognitive diagnosis: normal (n=9), amnestic MCI single domain (n=4), amnestic MCI multiple 
domain (n=10), and dementia (n=11). A univariate linear regression was used to test for differences in the 
mean plasma biomarker levels across the cognitive diagnoses. Although the tests did not reach statistical 
significance (p<0.05), there are appreciable differences between persons with normal cognition and 
dementia for NFL and tau. Persons with dementia had 81% higher mean NFL and 37% higher tau as 
compared with persons with normal cognition. Data from ADNI also suggests higher plasma tau102 and 
 

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plasma NFL106 levels in participants with dementia compared to cognitively healthy controls. Thus, we 
propose to use these plasma biomarkers in MAP and hypothesize metformin will have stronger effects on 
tau and NFL than on Aβ42/Aβ40 ratio.  
2.2.7.6.  We have experience with imaging of amyloid, tau, neurodegeneration (ATN) brain biomarkers.  
Dr. Luchsinger has successfully implemented imaging of ATN brain biomarkers in currently funded grants 
(R01AG050440; RF1AG051556; R01AG055299). These studies are funding brain magnetic resonance 
imaging (MRI), amyloid (18F-florbetaben, 11C-PIB) positron emission tomography (PET) scans, and tau (18F-
MK-6240) PET scans in community dwelling participants with an average age of 64 years. As of 10/28/19 
we had completed 477 amyloid PET scans and brain MRIs, and 304 tau PET scans. Dr. Luchsinger has 
investigational new drug (IND) protocols approved by the FDA for the use of 18F-MK-6240 for brain tau 
imaging with PET (137,482) and 11C-PIB for brain amyloid imaging with PET (142,117).  
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS AND THEIR MITIGATION 
Quality and risk management plan 
To mitigate risks, an Integrated Quality & Risk Management Plan has been developed.  The plan provides 
a summary of highest-scoring risks: delay in investigational products availability; failure to meet 
enrollment target; and high rate of missed assessments. In addition, the Risk Matrix provides details on 
risks to quality, along with mitigation strategies and risk scores. 
Risks from metformin  
Metformin is contraindicated in persons with an estimated glomerular filtration rate (eGFR) of less than 
30 mL/min. For persons with an eGFR of 30 to 45 mL/min, metformin can be continued with caution but 
a reduction of the dose or discontinuation of the medication can be considered; in this range, it is also 
recommended that persons do not initiate metformin. Thus, participants with eGFR < 45 mL/min will not 
be eligible to participate. The risk of lactic acidosis is increased in persons with liver disease and class III 
or IV congestive heart failure. Thus, persons with liver disease other than non-alcoholic-fatty liver disease 
or class III or IV congestive heart failure will not be eligible to participate due to the risks of side effects. 
Non-alcoholic fatty liver disease is allowed given that it may benefit from metformin, unless it is at the 
cirrhosis stage.  
Participants will be cautioned that IP be discontinued the day before any surgery or administration of 
contrast agents and may be resumed 48 hours after the procedure. We will monitor these contingencies 
on a monthly basis, and ad-lib as needed by the participant. We will also tell participants to avoid excessive 
intake or binge intake of alcoholic beverages. The Centers for Disease Control (CDC) define excessive 
alcohol intake as 15 drinks or more a week in men, and 8 drinks or more in women. The CDC defines binge 
Table 5. Unadjusted means and standard deviations of plasma AD biomarker levels by cognitive diagnosis 
N 
Normal  
(n=9) 
aMCI-single 
domain (n=4) 
aMCI-multi 
domain (n=10) 
Dementia  
(n=11) 
p-trend 
p-value* 
NFL, pg/mL 
32 
20.10 (8.18) 
18.23 (17.09) 
17.12 (12.45) 
36.50 (32.46) 
0.132 
0.097 
Tau, pg/mL 
31 
2.94 (1.26) 
2.79 (0.72) 
3.33 (1.47) 
4.03 (2.18) 
0.146 
0.191 
Ab40, pg/mL 
31 
311.16 (69.36) 289.55 (81.89) 
279.18 (87.11) 
351.47 (115.96) 0.421 
0.392 
Ab42, pg/mL 
30 
13.10 (4.69) 
11.89 (2.50) 
11.44 (4.11) 
15.61 (5.14) 
0.333 
0.272 
Ab42/Ab40 ratio 
30 
0.042 (0.008) 0.042 (0.006) 
0.040 (0.005) 
0.044 (0.005) 
0.617  
0.517 
Data are mean (SD), *p-value for test of significant differences between dementia and normal groups  

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drinking as 5 or more drinks consumed on one occasion for men, and 4 or more drinks consumed in one 
occasion for women. The United States standard drink sizes are 12 ounces of 5% alcohol by volume (ABV) 
beer, 8 ounces of 7% ABV malt liquor, 5 ounces of 12% ABV wine, and 1.5 ounces of 40% ABV (80-proof) 
distilled spirits or liquor (e.g., gin, rum, vodka, whiskey).  
Hypoglycemia should not occur because participants are not diabetic and should not be on other diabetes 
medications. If participants develop diabetes by HbA1c criteria (6.5% or higher) they will be referred to 
their physicians to decide about treatment for diabetes. This may lead to discontinuation of IP upon 
consultation with the study’s safety officer at the DCC. However, participants will be invited to remain in 
the study and will be analyzed following intent to treat. We will call these participants every month to 
follow-up. 
As mitigation, B12 levels, complete blood count, hepatic function, and kidney function will be tested every 
six months. Development of suspected side effects or contraindications to metformin will lead to stoppage 
of the medication upon consultation with the medical monitor. 
We will call participants every month to ask about side effects such as the following: 
• 
Very common (>1/10) 
o Gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain, and loss of 
appetite.  
These undesirable effects occur most frequently during initiation of therapy and resolve 
spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal 
tolerability. Gastrointestinal disorders are the most common reason for metformin non-tolerance.  
• 
Common side effects (>1/100):  
o Taste disturbance. 
• 
Very rare side effects (<1/10,000):  
o The most severe but very rare side effect of metformin is lactic acidosis.  
o Metformin has also been reported to cause vitamin B12 (cobalamin) malabsorption and decrease 
in serum levels that can lead to megaloblastic anemia.  
o Liver function abnormalities 
o Skin reactions such as erythema or pruritus 
o Tachycardia 
Adequacy of protection against risks 
a. Informed Consent 
Potential participants may contact the study coordinator/research assistant, or the latter may contact 
potential participants using available contact information. The usual contact will be via telephone, but 
could include email, or mail. At first contact by telephone the study will be briefly explained and the 
interest to participate will be explored. If the individual wants to participate, he/she will be screened for 
inclusion and exclusion criteria. If the individual is eligible, an appointment for a screening visit will be 
made. At that time, the consent form will be reviewed and if appropriate, signed by the participant and 
coordinator. A copy of the consent form will be provided to the participant for his or her records. The 
consent form will specifically request consent for the future use of data and stored serum and plasma for 
ancillary studies. 
b. Protections Against Risk 
Privacy/confidentiality. The EDC will automatically assign each participant with an ID number that will be 
used for all study documents. 
Risks from neuropsychological testing  

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Participants will be clearly told as part of the written consent and verbally that they can opt out of the 
study at any time if they do not wish to carry out the testing. We will reschedule the testing as desired by 
participants if they wish to continue. 
Risks from interviews  
The interviews and cognitive testing may cause psychological distress in participants. Our staff in charge 
of data collection will be bilingual as needed, trained in cultural competence and have at least 3 years of 
experience in the administration of cognitive batteries. We have never had to respond to a contingency 
or complaint related to the administration of interviews or cognitive testing.  
Risks from physical assessments  
The measurement of vital signs and anthropometrics may cause psychological distress and physical 
discomfort.   
Risks from phlebotomy 
The total amount of blood drawn for clinical diagnostic evaluation will not exceed 60 mL. Venipuncture 
could result in transient discomfort, pain, bleeding, an ecchymosis (a.k.a. bruising), and in the worst-case 
scenario, a hematoma. Significant bleeding is highly unlikely in the absence of a bleeding or coagulation 
disorder. The study personnel will be instructed to maintain pressure with gauze on the venipuncture site 
for at least 10 minutes. In the case of persistent bleeding, the investigators will be called immediately. A 
hematoma is highly unlikely, but in a worst-case scenario could result in a compartment syndrome.  
If participants report any discomfort or complication from phlebotomy or other physical assessment (e.g., 
hematoma), site PIs or study physicians will be called immediately to assess the problem and decide on 
further actions including referral to the emergency room. 
Risks from brain imaging procedures  
We will exclude from the study any participant who reports contraindications to MRI. If a participant 
becomes anxious and cannot complete any imaging procedures, or if a contraindication is found at the 
time of the imaging procedures, they will be excluded from undergoing brain MRI. Brain MRI may show 
abnormalities during a safety read conducted by a site radiologist within 24 hours of the scan. These 
findings are communicated to site investigators who take the appropriate action. Incidental MRI findings 
are classified in four levels following a standard protocol: 
• 
Level 1: No medically significant findings. No referral necessary. 
• 
Level 2: Minor findings without medical significance (e.g., white matter hyperintensities). No referral 
necessary. 
• 
Level 3: Expedited, but non-urgent medical evaluation recommended within 2 weeks (e.g., apparent 
meningioma without signs of mass effect). 
• 
Level 4: Acute abnormal findings requiring immediate medical attention (e.g., acute stroke or space 
occupying lesion with mass effect). 
The estimated total radiation a participant will receive from the maximum of 2 PET scans repeated after 
approximately 18 months is 24.88 mSv (including the radiation of the 2 injections of florbetaben and MK-
6240 and the radiation from the 2 CT scans, repeated after 18 months), similar to the radiation that the 
average person in the United States is exposed to in 48 months (4 years). 
Potential risks from MRI. All participants willing to undergo MRI will be questioned for exclusion criteria, 
including claustrophobia and the presence of foreign bodies not acceptable for MRI. While there have 
been no reports of any harmful long-term effects caused by a 3.0 T magnet, or magnets of even higher 

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strength, the long-term effects of being placed in a magnet of this strength are not known.  Some people 
may experience nervousness or discomfort due to the scanner’s small space and the need to lie still during 
the scans. Other than for pacemakers, some types of metallic implants and medication patches (which are 
contraindications to MRI participation), we are not aware of any other potentially dangerous interactions 
with the MRI scan. Since the MRI scanner produces loud “knocking” noises; participants will be provided 
with earplugs for their comfort. If any discomfort is experienced and participants wish to stop the scan, 
they can inform the MRI technologist and the scan will be stopped immediately. In our experience, no one 
has had ongoing sensations from the MRI scan once the scanning has stopped. 
Potential risks from PET scans. The risks from PET scans include risks from phlebotomy, similar to those 
described above, and from exposure to radiation. The procedures involving radiation in this research study 
will expose each participant to a very small amount of radiation (24.88 mSv total for the maximum of two 
florbetaben scans and two MK-6240 scans over approximately two years), in addition to the amount that 
they might receive from normal medical care. There may be an increase in the chances of developing 
cancer many years after this study. The additional risk from this research study is less than 0.15% (1 in 
705). At this very low level, scientists are uncertain as to the actual risk from research and there may be 
no risk at all. 
Risks to confidentiality 
Health Insurance Portability and Accountability Act (HIPAA), and data safety and security: only the PI and 
approved study personnel will have access to individually identifiable private information. 
ID assignment. In compliance with HIPAA, individual participant confidentiality is assured through the use 
of ID codes. These ID numbers will be automatically assigned by the EDC (managed by the DCC) and will 
not contain protected health information (PHI) (e.g., social security number, medical records number, 
etc.). Case report forms will be identified only by ID numbers. Data processing and analyses will not permit 
identification of any individual. Linkage between individual and ID number will only be accessible by site 
personnel and the monitoring personnel. 
Data transfer. It is assumed that all PHI will be collected after informed consent; as a result, certain PHI 
(e.g., date of birth) that are necessary for analyses may be entered as part of the data set.  
Monitoring risks 
Routine monitoring of study data will take place to ensure timely entry of study data, data quality and 
data integrity. The monitoring team will compile and track the following quality metrics:  
• 
Major protocol violations – number of major protocol violations per participant at a site and the 
total count of violation divided by the number of participants in the study. 
• 
Major audit findings – number of major audit findings per site and across the sites in the study. 
• 
Time to query resolution – the average number of days between query issuance and resolution on a 
per-site and overall study basis. 
• 
Visit entry time – the average time within a site for entry of visit data, calculated as elapsed days 
between the Date of Screening/Date of Visit and the first date that the status of that page was set to 
IN REVIEW. 
• 
Actual vs. planned spending – the ratio of actual costs (both quarterly and annual) as a percentage 
of the planned budget for that year.  
• 
Enrollment rate – the rate of enrollment by site and for the entire study, annualized and normalized 
by the duration of a site’s participation to allow cross-site comparisons. Specifically, RND/Site-Year is 
calculated as #RND*365/#days elapsed since site activation. 

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• 
Missingness rate – the number of missed data points divided by the number of expected data points 
given the participants’ status and progress. The denominator is difficult to calculate in an automated 
manner; a visual estimate on a sampling of participants is sufficient for the purposes of assessing site 
data quality. 
• 
Query rate – the number of queries for a site divided by the number of case report form (CRF) pages 
accrued by the participants at that site as of a specific point-in-time. 
Addressing medical and mental health contingencies. It is possible that during a study visit the staff or 
investigators encounter a medical contingency. The Table of Medical Contingencies (below) describes the 
protocol for such contingencies. 
 
CONDITION 
ACTION 
Blood pressure problems as reported by participant 
High or low blood pressure 
Refer to emergency room/call 911, or walk-in PMD’s office 
immediately 
Diabetes 
If dizzy and/or hypoglycemic by fingerstick 
Administer juice, other sweet beverage, or food by mouth; if 
improved within 15 minutes, advise to consult with PMD the 
same day; if not better, refer to 
emergency room/call 911 
Complaining of polydipsia 
polyuria, FS >200 mg/dl 
Refer to emergency room/call 911 
 
FS >200 mg/dl and 
asymptomatic 
If treatment has not been taken, advise to take it 
If treatment has been taken, advise consultation with PMD the 
same day 
Falls 
Fall during motor assessment or any other 
circumstance 
Call PI or study physician; take to emergency room. 
 
Respiratory 
Chest pain 
If cardiac etiology cannot be ruled out clinically, refer to 
emergency room/call 911 
If accompanied by diaphoresis or respiratory distress, refer to 
emergency room/call 911 
If chest pain clearly not cardiac, consultation with PMD the 
same day 
Asthma/COPD exacerbation 
 
If improved with treatment available at home, consultation 
with PMD the same day. 
Otherwise, refer to emergency room/call 911 
Other respiratory distress 
Refer to the emergency room/call 911 
Psychiatric/social 
Depression/anxiety 
If no potential harm to self or others, consult with PMD or 
mental health provider the same day 
Take prescribed medications not already taken 
If potential harm to self or others, refer to the emergency 
room/call 911 
Any condition with acute changes in mental 
status 
Refer to the emergency room/call 911 
 
Neglect 
If potential harm to self-apparent within 24 hours, refer to 
emergency room/call 911 
If medical condition suspected as cause, refer to emergency 
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CONDITION 
ACTION 
In other situations, notify social worker and next of kin 
Other 
Leg edema 
If acute, refer to emergency room/call 911 or walk-in clinic  
If sub-acute, consult with PMD the same day 
Failure to thrive 
Refer to emergency room/call 911 
Apparent dehydration 
Refer to emergency room/call 911 
Fever 
Consultation with PMD the same day 
Vomiting/diarrhea 
If unable to hydrate by mouth, refer to emergency room/call 
911; otherwise, advice consultation with PMD the same day. 
Withhold study medication until vomiting and diarrhea have 
stopped, and dehydration has resolved. 
Headache 
If clearly migraine or tensional headache, advise to take 
prescribed medications; if no improvement, consult with PMD 
same day. 
If no changes in mental status or neurologic deficits, if blood 
pressure <160, consultation with PMD same day; otherwise, 
refer to emergency room/call 911 
Weight loss/no medical 
follow-up 
Consult with PMD the same day 
If no PMD, see contacts below 
Acute renal insufficiency (azotemia), for any 
reason, 
including 
post-renal 
(e.g., 
obstruction), pre-renal (e.g., dehydration), or 
intrinsic (e.g., acute tubular necrosis)  
Stop IP until the cause of acute renal insufficiency has resolved 
and renal function has improved to at least a GFR of 45 mL/min 
or higher 
Any other condition treated 
Advise consultation with MD. Provide contact numbers (see 
below) 
IF IN DOUBT 
Contact PI or study physician 
Table 6. Medical Contingencies: Summary of Conditions and Actions 
Vulnerable participants 
No vulnerable populations will be included in this study. 
2.3.2 POTENTIAL BENEFITS  
Metformin may improve the risk of diabetes and improve features of the metabolic syndrome. 
Potential benefits of the proposed research to participants and others 
In principle, participants will not derive any benefits from participation in the study. However, participants 
will undergo actionable blood tests at screening and during follow-up that might uncover an underlying 
medical problem not related to the study that might otherwise gone unnoticed. We will share study 
results with participants, who in turn will be able to share the results with their physicians. If participants 
do not have a primary physician and need guidance, the site PIs will facilitate referral to a primary care 
physician at each of the study sites. The results of brain MRI will not be shared with participants. However, 
if there are level 3 or 4 findings, participants will be notified as soon as possible by the pertinent site PI or 
designated physician. Level 3 findings require evaluation that is not urgent. Level 4 findings require urgent 
evaluation and possibly an immediate emergency room referral. Participants on metformin may derive 
metabolic benefits and desired weight loss from participation in the study. The benefit to others comes 
from learning about whether metformin can prevent Alzheimer’s dementia. 
Importance of the knowledge to be gained 

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MAP is responsive to NIA’s Funding Opportunity Announcement PAR-18-028 “Phase III Clinical Trials for 
the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline”. MAP addresses the following 
example of interventions listed in PAR-18-028 “repurposed drugs that have promise for AD treatment 
such as chemotherapeutic agents or drugs for insulin dysregulation/diabetes. MAP is responsive to goal 1 
of the National Plan to Address Alzheimer’s Disease to “Prevent and Effectively Treat Alzheimer’s Disease 
and Related Dementia by 2025”. There are no known preventive or curative strategies for Alzheimer’s 
disease at the moment. Recent clinical trials of amyloid based therapies have failed. MAP provides an 
opportunity to test a medication that has metabolic benefits and a low-risk side effect profile for the 
prevention of the cognitive declines associated with conversion to Alzheimer’s dementia among persons 
with prodromal Alzheimer’s dementia. 
3 
OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
1. To compare changes from 
baseline to 18 months in 
verbal memory performance, 
measured with the Total 
Recall Score of the FC-SRT, 
between the metformin and 
placebo arms, following an 
ITT approach.  
Changes in Total Recall Score of the 
Free and Cued Selective Reminding 
Test (FC-SRT) 
The justification for using the FC-SRT 
as the primary outcome is that a 
similar test of verbal learning, the 
SRT, was the co-primary outcome in 
the MetMCI study that demonstrated 
a difference between the metformin 
and placebo arms. The FC-SRT is a 
more advanced version of the SRT 
that is sensitive to memory changes 
in prodromal Alzheimer’s disease.132 
Secondary 
 
 
1. We will examine global 
cognitive performance, 
measured with the ADCS-
PACC, as a secondary 
outcome.  
Changes from baseline to 18 
months in global cognitive 
performance, measured with the 
ADCS-PACC score, a composite that 
includes 4 tests: The FC-SRT, 2. The 
Delayed Recall score on the Logical 
Memory IIa subtest from the 
Wechsler Memory Scale, The Digit 
Symbol Substitution Test score, 
from the Wechsler Adult 
Intelligence Scale–Revised, and the 
Mini Mental Status total score.   
The ADCS-PACC is being used in 
clinical trials in persons with 
prodromal AD.  
2. To compare changes in 
neurodegeneration, 
ascertained as cortical 
thickness ascertained on 
brain MRI from baseline to 
18 months between 
metformin and placebo. 
Changes from baseline to 18 
months in cortical thickness 
ascertained on brain MRI 
 
 Cortical thickness is a measure of 
neurodegeneration.  
3. To compare changes in 
cerebrovascular disease, 
ascertained as WMH volume 
on brain MRI, from baseline 
Changes in from baseline to 18 
months in cerebrovascular disease, 
ascertained as white matter 
WMH is a measure of cerebrovascular 
disease.  

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
to 18 months between 
metformin and placebo. 
hyperintensities (WMH) volume (in 
mL) on brain MRI. 
4. To compare changes in brain 
amyloid from baseline to 18 
months between the 
metformin and placebo 
arms.  
Changes from baseline to 18 
months in whole brain Ab 
standardized uptake value ratio 
(SUVR) and in incident amyloid 
positivity 
whole brain Ab SUVR is a marker of 
in-vivo brain amyloid burden 
5. To compare changes in brain 
tau burden from baseline to 
18 months between the 
metformin and placebo 
arms. 
Changes from baseline to 18 
months in tau SUVR in a composite 
brain region comprising medial and 
inferolateral temporal cortex 
tau SUVR in a composite brain region 
is a biomarker of in-vivo brain tau 
6. To compare changes in AD   
plasma biomarkers, between 
metformin and placebo 
during follow-up 
Changes from baseline to 18 months 
in plasma AD biomarkers. These 
biomarkers will be measured in 
plasma from baseline and months 6, 
12 and 18 
AD plasma biomarkers are markers of 
neuropathology. 
Exploratory 
 
 
1. To examine APOE-ε4 genotype 
and COVID 19 history as a 
modifier of the interventions. 
All outcomes listed above. Persons 
without an APOE-e4 allele will be 
compared with those homozygous 
or heterozygous for APOE-e4. 
COVID-19 history will be 
ascertained by self-report.  
 
Primary and secondary endpoints. 
Previous studies have demonstrated a 
higher risk of dementia among 
persons with hyperinsulinemia who 
are heterozygous or homozygous for 
APOE-ε4. COVID-19 may cause long 
term cognitive sequelae that could 
affect the effectiveness of metformin. 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
We propose to conduct a phase II/III, multisite 1:1 randomized double-blinded placebo-controlled trial of 
extended-release metformin (maximum dose of 2,000 mg, four Glucophage XR 500 mg tabs [reduced 
mass]) in 326 men and women, aged 55 to 90 years of age, with amnestic mild cognitive impairment 
(including early and late amnestic mild cognitive impairment).  The trial will last 18 months. After 
screening for eligibility and consent, participants will have a baseline visit, followed by randomization to 
metformin or matching placebo, and a titration phase. Metformin (or matching placebo) will be titrated 
from 500 mg a day to 2,000 mg a day at increments of 500 mg every 10 days, as recommended by the 
manufacturers. Participants will be seen every 6 months thereafter for study assessments. Study 
procedures will include phlebotomy and laboratory tests, general health questionnaires, 

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neuropsychological testing, physical exam comprising a brief neurologic exam, measurement of vital signs 
and anthropometric measures. Study partners will also undergo questionnaires. Up to 186 participants 
will undergo brain magnetic resonance imaging (MRI) before IP is initiated (a window of two months is 
allowed to complete brain imaging), and after the last assessment at 18 months. Similarly, up to 186 
participants will undergo amyloid and tau Positron Emission Tomography (PET).  MAP will be a multisite 
study.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Alzheimer’s dementia is a common disease with no current cure. One in ten Americans over the age of 65 
years will develop Alzheimer’s dementia. Participation in this study will help advance knowledge of this 
disease. It is unknown if metformin will prevent cognitive decline associated with Alzheimer’s dementia.  
A control group administered placebo is necessary to determine if changes in verbal memory 
performance, as measured with the FC-SRT and global cognitive performance, as measured with the 
ADCS-PACC, are related to the use of metformin or not.  The placebo control group will not be subject to 
risks greater than the intervention arm. 
4.3 
JUSTIFICATION FOR DOSE 
The justification for the dose is that it is the maximum approved dose for the treatment of diabetes, also 
used off label for diabetes prevention among persons at risk.  
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last visit or the last scheduled procedure shown in the flow diagram in Section 1.2 Schema. 
The end of the study is defined as completion of the last visit or procedure by all participants. 
5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
• 
Diagnosis of aMCI: in general, the diagnosis of aMCI follows the definition in the 2011 National 
Institute on Aging (NIA)/ Alzheimer’s association (AA) guidelines, without biomarkers.133  Participants 
must have: 
o Subjective memory concerns reported by the participant, study partner, or clinician.  
o A mini-mental state exam ≥ 22 for participants with more than 8 years of education. For 
participants with less than 8 years of education, a MMSE ≥ 20 will be allowed. 
o Clinical Dementia Rating (CDR) = 0.5. The memory box score must be at least 0.5. Information 
from the formal University of Washington CDR instrument, report by the participant of 
subjective cognitive complaints, and findings from the screening neuropsychological battery, 
can be used for this determination by the investigative team. For example, the University of 
Washington CDR can be 0, but the CDR memory box score can be deemed to be 0.5 based on 
cognitive complaints at screening and meeting the MCI neuropsychological criteria. 
o General cognition and functional performance sufficiently preserved such that a diagnosis of 
dementia cannot be made by the site physician at the time of the screening visit.  

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o Abnormal memory function documented by scoring within the education adjusted ranges on 
the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler 
Memory Scale-Revised.  
 
For early MCI: 
9-11 for 16 or more years of education 
5-9 for 8-15 years of education 
3-6 for 0-7 years of education 
 
For late MCI  
≤ 8 for 16 or more years of education 
≤ 4 for 8-15 years of education 
≤ 2 for 0-7 years of education 
• 
Age range: 55 years to 90 years.  
• 
Sex distribution: all eligible men and women will be included, and no one will be excluded because 
of gender. 
• 
Languages: fluent in English or Spanish.  We have reliable, well-validated Spanish tests for all outcome 
measures. 
• 
Participants without a known history of diabetes. If diabetes is diagnosed during screening 
(hemoglobin A1c [HbA1c] of 6.5% or greater) participants will be excluded.  The main justification for 
this exclusion is the potential for these participants to be placed on other diabetes medications that 
may confound our study.  
• 
General cognition and functional performance such that a diagnosis of dementia cannot be made at 
the time of screening based on DSM-V criteria.  
• 
Vision and hearing must be sufficient for compliance with testing procedures.  
• 
Must have a study partner to come to all appointments or be available by telephone at follow-up 
visits.  
Study Partner Inclusion Criteria 
• 
The study partner can provide an independent evaluation of functioning for a person enrolled in the 
MAP study as a participant. 
• 
The study partner agrees to attend study visits with the MAP participant or be available by telephone. 
5.2 
EXCLUSION CRITERIA 
• 
Use of metformin or any class of medication approved for the treatment of diabetes,134 even if it is 
used for an  indication other than diabetes (e.g. obesity), within 1 year of screening. These 
medications include GLP-1 agonists used for weight loss. 
• 
Body mass index < 20 k/m2. 
• 
Metformin is contraindicated in persons with an estimated glomerular filtration rate (eGFR) of less 
than 30 mL/min. For persons with an eGFR of 30 to 45 mL/min, a reduction of the dose or 
discontinuation of metformin may be considered. It is also recommended that persons do not initiate 
metformin in this range. Thus, participants with eGFR < 45 mL/min will not be eligible to participate. 
• 
The risk of lactic acidosis is increased in persons with liver disease and class III or IV congestive heart 
failure. Thus, persons with liver disease other than non-alcoholic-fatty liver disease or class III or IV 
congestive heart failure will not be eligible to participate due to the risks of side effects. 

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• 
A history of intolerance to metformin. 
• 
History of cerebrovascular accident with residual neurological deficits.  
• 
Moderate to severe depression, indicated by a score in the Geriatric Depression Scale of 9/15 or 
higher.  
• 
Dementia diagnosis 
• 
Lack of capacity to consent 
• 
Participants with neurologic diseases associated with neurologic deficits on clinical examination.  
• 
Participants with other current Axis I psychiatric diagnoses such as bipolar disorder or schizophrenia.  
• 
Alcohol or substance abuse or dependence in the past 6 months. 
• 
Use of medications rated as being the likely cause of cognitive impairment. These include 
benzodiazepines in dose equivalents greater than 2 mg daily of lorazepam, and regular use of 
prescription narcotics. 
• 
Normal individuals without cognitive complaints.  
• 
Participants with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 95 mmHg). 
• 
Participants with active cancer or a history of cancer within the last two years, with the exception of 
squamous or basal cell carcinoma of the skin. 
• 
Participants who for any reason may not complete the study as judged by the study physician. 
• 
Participants planning to move to another city or state during the duration of the study.  
• 
Participants with a known history of diabetes. The rationale for this exclusion is persons with diabetes 
may already be on metformin or on other medications that increase insulin levels and could confound 
the trial.  
• 
Participants with diabetes discovered on screening based on American Diabetes Association criteria 
using HbA1c (HbA1c of 6.5% or greater). Although metformin could be a first treatment of diabetes 
for these participants, addition of treatments for diabetes by physicians could confound the study.  
• 
Use of any amyloid modifying treatment for AD such as lecanemab, either experimental or approved 
by the Food and Drug Administration, is exclusionary. Previous use of amyloid targeting therapy that 
was shown to be non-efficacious (e.g. solunazemab) is not exclusionary.  
• 
Not able to undergo phlebotomy as reported by the participant or determined by the study 
coordinator or physician.  
• 
Participants with known, suspected, or plan for becoming pregnant. 
• 
The presence of a medical condition, and/or use of a medication and/or any substance, individually 
or in aggregate, that in the judgement of the study team, is the primary cause of cognitive 
impairment. For example, if hypothyroidism, cobalamin deficiency, or tertiary syphilis are reported 
or found during screening, they could be deemed as being likely contributors to cognitive 
impairment, and thus be exclusionary. Combinations of multiple medications with anti-cholinergic 
effects with or without other central nervous system depressants could also be considered as being 
causative of cognitive impairment and exclusionary.  
Exclusion Criteria for MRI 
Contraindications for MRI include inability to lie flat, claustrophobia, or presence of indwelling metal 
objects or implants that are not MRI compatible. 
Exclusion Criteria for PET 

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History of adverse reactions to radiocontrast agents. 
5.3 
LIFESTYLE CONSIDERATIONS 
Participants will be informed that the risk of complications from metformin, particularly lactic acidosis, 
can increase with excessive alcohol intake. In addition, study medication should be stopped in other acute 
conditions that could lead to lactic acidosis, including diarrhea and vomiting, acute renal failure, and 
hospitalizations for acute infection that could lead to sepsis or involve sepsis. IP may be resumed when 
these situations have resolved.  
5.4 
SCREEN FAILURES 
Screen failures will be excluded from the study.  
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
To ensure the trial accrues and retains the number and diversity of participants required to assess the 
primary and secondary endpoints, a recruitment and retention risk and needs assessment to identify areas 
of concern and opportunities for engagement will be conducted. Our approach will recognize and support 
the diverse needs of study sites (clinicians, research staff, and informatics staff), meaningfully involve 
participants, families, community groups and clinicians in all stages of the study. Site-specific recruitment 
planning will be done with guidance from the master recruitment and retention plan allowing adaptation 
to the sites’ local IRB requirements and institutional marketing practices. We will use an ongoing 
evaluation process, which will include iterative feedback from the recruitment reports, sites, and study 
participants and will guide implementation activities and adapt as needed. A portfolio of recruitment 
materials such as flyers, posters, phone and email scripts, and social media ads will be available to be 
personalized for local sites. All recruitment materials and scripts will be approved by the IRB prior to use. 
These assets will be available electronically. Each participating site will be able to choose recruitment and 
retention strategies that fit their local setting such as: 
• 
Broad targeted advertisements (e.g., brochures/flyers, web advertisements and notices, social 
network advertisements including but not limited to Facebook, Twitter and Instagram, and media 
advertisements on television, radio and newspapers). 
• 
Direct-to-participant (e.g., mail, health system portals, calls, waiting rooms, or clinical team) 
• 
Social and community networks (e.g., social media, support group newsletters or community events) 
Potential strategies to be employed regarding screening and recruitment include: 
Pre-Screen/Screening 
• 
Phone calls will be made to potential participants identified through EHR, registries, and those who 
respond to ads.  
• 
Unsolicited “cold calls” to potential participants will only be made at sites where this practice is 
approved by the local IRB.  If approved, the study coordinator will use the Telephone Screening Script 
to discuss the study with the potential participant. 
• 
If unsolicited “cold calls” are not permitted by the local IRB, such calls will not be conducted. 
• 
An alternative to the unsolicited “cold call” is the use of MyChart (an Epic EHR product) or similar 
EHR-based communication tool.  Use of EHR based communication will only be conducted based on 
local site practices and with local IRB approval.  The communication text is outlined in the document, 
EHR-based Recruitment Communication. 

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• 
Potential participants will be encouraged to share study information and study contact phone 
number or website with friends/family who may interested in participating in the study 
• 
Potential participants will be asked for recommendations on possible recruitment sites. 
• 
Potential participants will be invited to register on Alzheimer’s registries, general research 
recruitment registries including but not limited to ResearchMatch 
• 
Potential participants will be asked, “How did you hear about the study?” 
• 
Additional centralized pre-screening may occur through recruitment websites using a dedicated call-
in center at Columbia University. 
 
Consenting 
• 
Potential participants will be given opportunities to ask questions about study 
• 
Recruitment and retention team members will begin building rapport with participants 
• 
Medical care providers will be informed of participant enrollment (when possible, or as required) and 
provided with study brochure or one-page flyer. 
Potential strategies to promote engagement and retention of participant could include: 
• 
Return of laboratory results 
• 
Phone calls 
• 
Reminder cards 
• 
Holiday Birthday cards 
• 
All participants and study partners will be offered a perk for participation, such as an Amazon Prime 
membership for the duration of the study or a gift card of similar value. 
The DCC and CCMC will compile reports to generate a master log of participant attrition and missed visits. 
This log will be monitored to guide and inform continuous process improvement.  
6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
There will be 2 study arms, extended-release metformin (Glucophage XR 500 mg tablets [reduced mass]; 
2,000 mg a day maximum dose), and matching placebo with identical appearance. IP will be supplied by 
EMD Serono Research & Development Institute and delivered in bulk to the research pharmacy at the 
University of Iowa, which will prepare bottles with IP. These will be sent to the University of Rochester, 
which will prepare kits of IP for dispensation. The University of Rochester will send these kits to the local 
pharmacies of participating clinical sites for dispensation.  
6.1.2 DOSING AND ADMINISTRATION 
IP will be titrated every 10 days by one tablet (500 mg), up to 2000 mg a day. Participants will remain in 
the study on the maximum tolerated dose and will be considered in the analyses on an intent to treat 
basis.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 

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6.2.1 ACQUISITION AND ACCOUNTABILITY 
The central research pharmacy for the study will be located at the Clinical Materials Services Unit (CMSU) 
at the University of Rochester. The University of Iowa Pharmaceuticals (UIP) will receive Glucophage XR 
500 mg tablets [reduced mass] and matching placebo in bulk (drums of 24,828 tablets for metformin, 
drums of 13,800 for placebo) from the EMD Serono Research & Development Institute, who will supply 
the IP. The UIP will prepare bottles of IP with a 140 count (35-day supply at maximum dose). The CMSU 
will receive approximately 4,900 x 140-count bottles each of metformin 500 mg tablets and matching 
placebo tablets from the UIP divided over three shipments. These quantities of study drug will support 
326 participants, randomized 1:1 (active:placebo) and includes an overage factor of 40% for baseline kits 
and 10% for resupply kits. Upon receipt of the investigational products, the CMSU will perform a visual 
inspection and quality assurance (QA) release of all incoming materials to confirm that the appropriate 
quantities were received in good condition. Using the randomization code provided by the DCC), the 
CMSU will generate the necessary bottle and kit box labels that will support the double-blind, 1:1 
(active:placebo) design of the study.  
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The CMSU will label the study drug and configure the 140-count bottles into six-month kits delivered to 
the site local research pharmacy containing two three-month kits with 3 bottles each. The study site local 
research pharmacy will dispense the study drug to participants by mail or will dispense the study drug to 
the CRC who will provide it to the participant at the in-person study visit or by mail. Study drug may be 
dispensed as two 3-month kits every six months or one kit every 3 months, whichever is preferred by the 
participant. The CMSU will generate the necessary bottle and kit box labels that will support the double-
blind, 1:1 (active:placebo) design of the study.  
Sites will maintain accurate records of study kits in the EDC inventory form. When inventory falls below 
par (periodic automatic replenishment) level, study kits will be replenished by CMSU.  
6.2.3 PRODUCT STORAGE AND STABILITY 
IP tablets are to be kept in the container in which they are supplied and are to be kept tightly closed. To 
protect young children from poisoning, we advise that safety caps be kept locked, and the medication be 
immediately placed in a safe location out of sight and reach of children. Tablets should be stored in the 
medication bottle at room temperature and away from light, excess heat, and moisture (not in the 
bathroom). Any unused tablets are to be returned to study personnel. 
6.2.4 PREPARATION 
For this study, the IP tablets will be prepared by the study pharmacy.  No preparation is required by study 
staff or study participants. The IP will be administered as an extended-release tablet taken by mouth, 
taken once daily with the evening meal. Participants will be instructed to follow the directions on the 
prescription label carefully and ask the doctor or study pharmacist to explain any part not understood. 
Participants will be instructed to take the IP exactly as directed and to not take more or less of it as 
prescribed by the healthcare provider.  The IP tablets are to be swallowed whole. They are not to be split, 
chewed, or crushed. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 

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Randomization: eligible participants will be randomized in 1:1 ratio to receive either metformin or 
placebo, using randomly permuted block randomization stratified by each site to achieve balance of 
treatment assignment overall and by site.  
Blinding: participants, providers, outcome assessors and biostatisticians will be blinded to the treatment 
assignment. One group of biostatisticians will be unblinded to the treatment assignment to provide 
reports to the MAP data and safety monitoring board (DSMB). 
6.4 
STUDY INTERVENTION COMPLIANCE 
Compliance with the study intervention will be monitored by direct discussion at monthly telephone calls 
and face-to-face study visits (every six months). 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant 
prescription medications (up to two months prior to baseline), over-the-counter medications and 
supplements. 
All concomitant prescription medications will be recorded in the CRF at screening and at each study visit 
as outlined in Table 7. Study Assessments and Procedures. 
6.5.1 RESCUE MEDICINE 
Not applicable 
7 
DISCONTINUATION OF STUDY INTERVENTION AND WITHDRAWAL OF PARTICIPANT 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation of IP does not mean discontinuation from the study, and remaining study procedures 
should be completed as indicated by the study protocol. If a clinically significant finding is identified 
(including, but not limited to changes from baseline) after enrollment, the investigator or qualified 
designee will determine if any change in participant management is needed. Any new clinically relevant 
finding will be reported. 
If participants develop diabetes by HbA1c criteria (6.5% or higher), they will be referred to their physicians 
to decide about treatment for diabetes. This may lead to discontinuation of IP upon consultation with the 
study’s safety officer at the DCC. However, participants will be invited to remain in the study and will be 
analyzed following intent to treat. 
If the medication is not discontinued due to an SAE and the investigator believes that the participant could 
be re-challenged with the discontinued medication per standard clinical practice, then this may be 
attempted after discussion with the DSMB and approval by the Medical Monitor.  
If the medication was discontinued due to an SAE, then there should not be an attempt to restart the 
medication.  
Any discontinuation of study drug will be recorded on the Dose Change Log eCRF. 

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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the CRF. 
Participants who sign the informed consent form (ICF) and are randomized but do not receive study 
intervention may be replaced. Participants who sign the ICF, are randomized, receive study intervention, 
and are withdrawn or discontinued from the study will not be replaced, and will be included in the final 
statistical analyses. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for two consecutive scheduled 
6-month-visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 30 days and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort 
to regain contact with the participant (where possible, three telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 The site will record the last date of contact (due to study completion, participant withdrawal from the 
study, or death) in the eCRF as the termination date.   
8 
STUDY ASSESSMENTS AND PROCEDURES 
The table below summarizes the study procedures during the 18 months of the study. There are 
procedures (questionnaires) that can be done remotely or in person, listed under the “Remote Module”, 
and there are procedures that can only be conducted in person, listed under the “in-person” module. The 
window to complete screening procedures is 28 days. The window for 6-month follow-up visits is ± 30 
days. The window for monthly contacts is ± 7 days. If a visit or contact is missed due to force majeure 
(e.g., hospitalization), a participant may continue in the study with the visit after the one missed. All brain 
imaging procedures should be conducted prior to starting study drug. Participants who completed the 18 
months visit before the implementation of protocol 1.9 will be informed of the change in study duration 
and that they have completed the study. Participants in this situation who are awaiting follow-up brain 

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imaging (originally after the 24-month visit) will be invited to undergo the brain imaging procedures as 
soon as protocol 1.9 is approved and implemented.  
 
Screening/ 
Baseline 
Titration 1,2, 3 
Month 1,2 
Month 3 
Month 4,5 
Month 6 
Month 7,8 
Month 9 
Month 10,11 
Month 12 
Month 13,14 
Month 15 
Month 16,17 
Month 18 
REMOTE MODULE 
1 
Telephone Screen 
X 
2 
UBACCa 
X 
3 
Remote Consent 
X 
4 
Demographicsf 
X 
5 
Medical historyf 
X 
6 
Medicationsb 
X 
X 
X 
X 
7 
MAC-Q 
X 
X 
X 
X 
8 
COVID-19 questionnaire 
X 
X 
X 
X 
9 
GDS 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
10 
CDR (Participant)c 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
11 
ADCS-ADL-PI 
(Participant) 
X 
X 
X 
X 
IN-PERSON MODULE 
12 
In-Person Consent (if 
not done remotely) 
X 
13 
Vital Signsd 
X 
X 
X 
X 
14 
Phlebotomyd 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
15 
Laboratory testsd 
X 
X 
X 
X 
16 
ECGd 
X 
17 
MMSE 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
18 
Paragraph Recall 
X 
X 
X 
X 
19 
Brief neurological exam 
X 
X 
X 
X 
20 
DSST 
X 
X 
X 
X 
21 
TMT A and B 
X 
X 
X 
X 
22 
Eligibility and 
Randomization 
X 
23 
FC-SRT 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
24 
MRI  
X 
X 
25 
Amyloid PET  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
26 
Tau PET   
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
27 
Titration 
X 
28 
Monthly Telephone Call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
29 
Drug Dispense 
X 
X 
X 
X 
X 
X 
30 
Dose Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
31 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
32 
Protocol Deviation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY PARTNER 
33 
Study Partner Consente 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
34 
CDR (Partner)c 
X 
X 
X 
X 
35 
ADCS-ADL-PI (Partner) 
X 
X 
X 
X 
36 
MBI 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
37 
Final Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Table 7. Study Assessments and Procedures 

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a: The UBACC test should only be performed if clinically indicated or if study personnel feel the participant does not have capacity 
to consent at any of the study visits, Screening included. Please refer to Section 8.1 for more information. 
b: The study team should take particular care to note if any diabetes medication has been taken during the study duration. 
c: A CDR will be completed with each study participant and their respective study partner at all visits (Screening/Baseline, Month 
6, Month 12, and Month 18). A total composite CDR score will be calculated using the sum of the CDR scores of both the 
participant and the partner. An ADAS-PAC certified team member should perform the CDR. 
d: Screening labs, vitals, and ECGs must be collected before randomization. Baseline labs, vitals, and ECGs do not need to be 
collected if performed within 14 days of the Baseline visit. All neuropsychological batteries, questionnaires, and the brief 
neurologic exam do not need to be performed again if collected during Screening. The screening tests will serve as the baseline 
collection. 
e: Study partners must provide verbal consent. The investigator or designee (consent designee) will read a consent script to the 
study partner and document that the study partner verbally consented to the MAP study. 
f: Study teams may stop screening assessments if the participant clearly does not meet eligibility.  
8.1 
EFFICACY ASSESSMENTS  
The study will have the following visits/calls: (1) telephone screening; (2) in person-screening and baseline 
study visit; (3) telephone calls for titration; (4) Follow up visits at months 6, 12, 18 months; (5) monthly 
calls between 6-month visits; (6) Brain Magnetic Resonance Imaging (MRI) at baseline and month 18. 
Primary and secondary clinical (non-MRI) efficacy data will be collected at baseline and the 6-month visits. 
Secondary MRI efficacy data will be collected at baseline and 18 months. The following is a brief 
description of these visits and the assessments included in these visits.  
1. Telephone screening. We propose a 2-tier approach for screening, including telephone pre-screening 
followed by in-person screening. Telephone screening includes questions about inclusion and exclusion 
criteria including demographics), social history, medical history, contraindications to metformin, and 
medications. Study sites have the option of conducting a telephone cognitive screen such as the TICS to 
exclude persons with normal cognition. 
Only persons who meet inclusion criteria and do not meet exclusion criteria are invited for in-person 
screening/baseline visit.  
2. In-person screening and baseline study visit.  In-person screening includes written informed consent, 
demographics, anthropometric measurements (height, weight, waist and hip circumference), vital signs 
(blood pressure and heart rate), EKG, laboratory tests (thyroid stimulating hormone [TSH], rapid plasma 
reagin [RPR], vitamin B12, complete blood count [CBC], basic metabolic panel [BMP], hepatic panel, lipid 
panel, and HbA1c), the neuropsychological battery, and a COVID-19 questionnaire. At the time of 
screening the tester will complete other assessments if the participant meets the neuropsychological 
criteria for MCI. All evaluations will be recorded in the eCRF, as applicable.  If the participant meets all the 
inclusion criteria and has no exclusion criteria, the participant will be randomized and mailed a 
randomization kit with IP. 
3. Telephone calls for titration. There will be 4 calls, one at the beginning of titration (one tablet a day), 
and 3 more calls every 10 days when the dose is increased by one tablet a day. During these calls, adverse 
events and tolerance will be documented.  
4. Follow-up visits at months 6, 12, and 18 will include data collection on anthropometric measurements 
(height, weight, waist and hip circumference), vital signs (blood pressure and heart rate), brief neurologic 
exam laboratory tests (vitamin B12, CBC, BMP, hepatic panel, lipid panel, and HbA1c), the 
neuropsychological battery, and the COVID-19 questionnaire. Adverse events and compliance will also be 
recorded. At the time of screening the tester will complete other assessments if the participant meets the 
neuropsychological criteria for MCI. All evaluations will be recorded in the eCRF, as applicable.   

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5. Monthly calls between 6-month visits: adverse events and compliance will be recorded 
6. Brain MRI will be conducted at baseline and 18 months.  
7. Amyloid PET will be conducted at baseline and 18 months.  
8. Tau PET will be conducted at baseline and 18 months.  
9. Plasma AD biomarkers will be measured in stored plasma from the 4 main visits (baseline and months 
6, 12, and 18).  
The following is a description of all assessments:  
Capacity to consent 
We will use the University of California, San Diego Brief Assessment of Capacity to Consent (UBACC)135 to 
assess capacity in the study. The UBACC is a 10-item scale that assesses understanding and appreciation 
of the information related to a research protocol. The UBACC will be available in English and Spanish.  It 
is important to point out that the study excludes participants with dementia at baseline (determined by a 
clinical dementia rating summary score of 1 or higher). Thus, all participants have in principle a cognitive 
status that allows for capacity to consent at baseline. There are two situations in which we will assess 
capacity to consent with the UBACC. 
• 
Throughout the study if the study staff appreciate that the participant does not comprehend the 
study information during the consent process regardless of cognitive status. At baseline, lack of 
capacity to understand the study will constitute a reason for exclusion. During follow-up assessments, 
determination of lack of capacity to consent will lead to the need for a legal authorized representative 
to consent after the participant provides assent to participate.  
• 
During follow-up, if the participant develops dementia, indicated by a clinical dementia rating 
summary score of 1 as determined in the previous follow-up assessment. If the participant 
demonstrates capacity, he/she may consent; if the participant lacks capacity but wants to continue 
participation, a legally authorized representative will need to provide consent after the participant’s 
assent. It is important to point out that this approach respects the participant’s decision at baseline 
to participate in the study, when he/she had the capacity to consent.  
Participants will be given three trials to respond to the UBACC. If after three trials they do not have a 
perfect score, they will be determined to lack capacity to consent. The determination of lacking capacity 
to consent will lead to exclusion at baseline, and to the need for a legally authorized representative to 
provide consent during follow-up. We expect that the contingencies described above will occur in less 
than 5% of the participants in the study, who will have mild cognitive impairment at baseline.  
Medical history, medications 
Detailed medical, surgical, and psychological history, and all medications utilized, including a judgment as 
to whether they affect cognition (positively or negatively) will be collected at baseline.  Psychiatric history, 
current and past history of depression, current anxiety, alcohol and other substance use, head injury, 
hypertension, cardiac disease, thyroid disease, other major medical conditions, and surgery are evaluated 
at the baseline visit.  A full medical history will be obtained only at the baseline visit. Any report of events, 
or side effects will prompt a full history and physical exam at follow-up visit. A COVID-19 questionnaire 
will be administered at every visit.  
Physical Assessments (vital signs, anthropometric measures, brief neurologic exam) 
A brief neurologic exam will be conducted at the in-person screening visit. Participants must also be 
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metformin. Vital signs including blood pressure and heart rate will be measured. Standing height will be 
measured using a stadiometer calibrated in cm. Body weight is measured using a balance beam scale 
calibrated in kg. With the participant standing, measurements are taken to the nearest 0.1 kg of weight 
with a balance scale and height without shoes to nearest 0.5 cm, to calculate BMI (weight in k/height in 
m2). Waist circumference (WC) is measured at the level of the umbilicus. Hip circumference (HP) is 
measured at the level of maximal protrusion of the gluteal muscles. Resting blood pressure (BP) will be 
measured using an automated oscillometric device; three measurements will be obtained at 1-minute 
intervals in a seated position after 5 minutes of rest. The average of the 2nd and 3rd measurements will 
be recorded. Vital signs and anthropometric measures will be repeated at all visits. A full physical exam 
will be repeated at follow-up visits only in the case of a change in medical history.  
Neuropsychological battery 
The following battery will be administered at baseline and 6-month visits. For neuropsychological testing, 
verbatim instructions for administration and specific scoring guidelines will be available. All instruments 
in the neuropsychological battery are commonly used, validated, published instruments.  Non-verified or 
unpublished instruments are not used in this research study.  All tests are validated in English and Spanish. 
We will use different versions of the tests when available (e.g., different word lists) to account for learning 
effects. The following is an expanded description of the neuropsychological battery:  
• 
Total Recall Score of the Free and Cued Selective Reminding Test (FCSRT). The FCSRT is a 16-item 
word list with visual and auditory presentation that uses semantic cuing to facilitate encoding and 
retrieval.  The test has a score range of 0 to 48.  
• 
Paragraph Recall on the Logical Memory IIa (episodic memory): Free recall of one short story that 
consists of 25 bits of information will be elicited immediately after it is read aloud to the participant 
and again after approximately 30-minute delay.  The total bits of information from the story that are 
recalled immediately (maximum score = 25) and after the delay interval (maximum score = 25) are 
recorded.  The delay score (0-25 story units) will be used in the composite and also for the inclusion 
criteria. 
• 
Digit-Symbol Substitution Test: The Digit Symbol Substitution test is a subset from the WAIS-R.  The 
test consists of 110 small blank squares presented in seven rows with one of nine numbers (1-9) 
randomly printed directly above each blank square.  A “key” is printed above the rows of blank 
squares.  The “key” pairs numbers 1 through 9 with an unfamiliar symbol.  The participant must work 
as fast as possible for 90 seconds.  The measure of interest is number of squares filled in correctly 
within the time limit (maximum raw score = 110).   
• 
Mini Mental Status Exam (MMSE). The MMSE scale evaluates orientation, memory, attention, 
concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two 
overlapping pentagons.  The MMSE is scored as the number of correctly completed items with a 
lower score indicative of poorer performance and greater cognitive impairment.  The total score 
ranges from zero (worse) to 30 (perfect). 
• 
Trail-Making Test, Part A:  This test of visuo-perceptual ability, attention and speed consists of 25 
circles distributed over a white sheet of 8 1/2" X 11" paper that are numbered. The participant is 
instructed to connect the circles with a pencil line as quickly as possible all numbers in an ascending 
order (e.g., 1 to 2; 2 to 3; etc.). The participant's performance is judged in terms of the time (in 
seconds) required to complete the task and by the number of errors of commission and omission.  
The time to complete the trial will be the measures of interest.  
• 
Trail-Making Test, Part B: This test of visuo-perceptual ability, attention and set-shifting ability 
consists of 25 circles distributed over a white sheet of 8 1/2" X 11" paper that either are numbered 

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(1 through 13) or contain letters (A through L). The participant is instructed to connect the circles 
with a pencil line as quickly as possible while alternating between numbers and letters in an 
ascending order (e.g., A to 1; 1 to B; B to 2; 2 to C). The participant's performance is judged in terms 
of the time (in seconds) required to complete the task and by the number of errors of commission 
and omission.  The time to complete the trial will be the measures of interest. Trail-Making Test, Part 
B is available in multiple forms of equal difficulty for purposes of repeated evaluations. 
• 
Functional abilities:  
o ADCS-ADL-PI: The ADCS-ADL-PI was developed in the ADCS Prevention Instruments Trial. The 
participant and study partner separately rate the participant’s performance of 18 IADL tasks over 
the past 2 months. Questions about use of technology (e.g., computers and cell phones) are 
included. Responses for each IADL include improved IADL performance (fewer errors, faster 
completion, less need to refer to notes or instructions), no change (‘as well as usual’), various 
levels of impaired performance, and non-performance.  
o Clinical Dementia Rating (CDR). The CDR is a clinical scale that rates the severity of dementia as 
absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively).  
The score is based on interviews with the participant and study partner, using a structured 
interview that assesses six domains:  memory, orientation, judgment and problem solving, 
community affairs, home and hobbies, and personal care.  The ratings of degree of impairment 
obtained on each of the six categories of function are synthesized into one global rating of 
dementia (ranging from zero to 3), with more refined measure of change available by use of the 
Sum of Boxes (CDR-SB).  Reliability and validity have been established, as has high inter-rater 
reliability.  
• 
Memory Complaint Questionnaire (MAC-Q): The MAC-Q consists of six items. The first five items 
relate to specific situations that are frequently reported as troublesome for those with declining 
memory, and the last item broadly measures overall self-perceived memory decline. 
• 
Mild Behavioral Impairment Checklist (MBI-C): the MBI-C is a rating scale for neuropsychiatric 
symptoms in a pre-dementia population. It has items in 5 domains: decreased motivation, emotional 
dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception or thought 
content. The MBI inquires about the presence of symptoms in these domains (yes, no) and their 
severity (mild=1, moderate=2, severe=3). It has 34 items in the 5 domains (maximum score =102). 
The MBI-C is administered to the study partner.  
• 
Geriatric Depression Scale (GDS): We will administer the 15 item GDS at all visits to assess depressive 
symptoms. The GDS has 15 yes/no questions assessing depressive symptoms.  
Brain imaging  
• 
Magnetic resonance imaging (MRI). We will acquire MP-RAGE and FLAIR imaging according to ADNI2 
specifications appropriate to site hardware and operating system. In addition, a Fast T2 Spin-Echo 
image will be acquired according to site hardware and operating system specifications for evaluation 
of MRI infarction and to exclude hemorrhage. Standard 2D sequence gradient echo imaging will be 
acquired to assess micro-hemorrhages as will multi-directional DTI to assess white matter integrity. 
These latter two image sequences will be standardized according to available hardware and operating 
systems and may be used for secondary analyses at a future date. The maximum imaging time will 
be 60 minutes. Following scan acquisition, the data are transferred to a PACS for clinical review of 
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• 
Amyloid PET: Amyloid PET imaging will be obtained using 18F-florbetaben. 18F-florbetaben will be 
injected as 8.1 mCi, with image acquisition 90-110 min post injection (following CT or transmission 
scan) as 4 x 5 min frames. 
• 
Tau PET: Tau PET acquisition will entail injection of 5 mCi of MK-6240 with imaging from 90-110 min 
after CT or transmission scan.136 
All brain imaging must be completed before study intervention is initiated. To this end, a window of 2 
months is allowed between enrollment and commencing titration of study drug to complete brain 
imaging procedures. For Brain MRI site qualification, a brain MRI with all sequences will be conducted on 
a volunteer, reviewed from an existing study, or evaluated by the MRI protocol based on the instructions 
provided during the study setup.  
Plasma biomarkers 
The plasma AD biomarkers will be measured using the commercially available ultrasensitive single-
molecule array (Simoa) assays.137 We will ship frozen plasma aliquots for these procedures at the end 
of data collection. Compared to the more commonly used ELISA methods, the Simoa assays provide high 
sensitivity and precision, while eliminating the matrix interferences.138 Tau, Aβ40, Aβ42 will be assayed 
together using a multiplex assay (Human Neurology 3-Plex Total). The Simoa Human Neurology 3-Plex 
Total Tau assay uses a combination of monoclonal antibodies that react with both normal and 
phosphorylated epitopes in the midregion of the molecule yielding an assay that is specific to all tau 
isoforms. With a mean range of 2.28-109 pg/mL, the lower limit of detection for tau is 0.02 pg/mL, the 
reproducibility coefficient of variation (CV) is 8.5% and repeatability CV is 7.7%.102,137 The Simoa Aβ40 and 
Aβ42 assays target the N-terminus of beta amyloid and different C-terminus detection antibodies specific 
to Aβ40 and Aβ42. Aβ42 (mean range: 0-400 pg/mL) has a lower limit of detection of 0.019-0.034 pg/mL, 
a reproducibility CV=7.5% and repeatability CV=6.7%.137,139-141 Aβ40 (mean range: 0-800 pg/mL) has a 
lower limit of detection of 0.16 pg/mL, a reproducibility CV=5.1% and repeatability CV=3.5%.98,141,142 A 
separate NFL test will be run using the ultrasensitive Simoa assay (mean range: 34.7-51.0 pg/mL and 
lower limit of detection of 0.97 pg/mL, CV=4.3%).106,143 Isolation and detection of single enzyme molecules 
using femtolitre-sized reaction chambers, known as Simoa. This method detects the target at low 
concentrations by ensuring that the fluorophores are confined to small volumes, and hence, the 
concentration of fluorescently labeled target is high. The antibodies are conjugated to magnetic particles 
utilizing a standard EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) coupling 
procedure. In the first step of the assay, antibody coated paramagnetic capture beads, biotinylated 
detection antibodies, and samples are combined, during which target molecules present in the sample 
are captured by the capture beads and labeled with the biotinylated detection antibodies. After 
washing, a conjugate of streptavidin-β-galactosidase (SβG) is mixed with the capture beads where SβG 
bound to the biotin, resulting in enzyme labeling of captured target molecules. Following a second 
wash, the capture beads are resuspended in a resorufin β-D-galactopyranoside (RGP) substrate 
solution and transferred to the Simoa array disc for detection. All samples will be diluted 4-fold for 
Aβ42 and 8-fold for Aβ40 using a proper sample diluent (PBS containing carrier protein and detergent) 
for measurement. Given the rapid advance in the field of plasma AD biomarkers,111 other biomarkers 
developed using the Simoa platform or other methods may replace or be added to those mentioned 
above.  
Cognitive diagnoses 
Cognitive diagnosis will be examined for inclusion and exclusion purposes and will also be examined as an 
exploratory outcome. For cognitive diagnosis transitions (i.e., conversion from MCI to dementia), an 
adjudication panel at the CCMC will conduct a meeting to arrive at a consensus regarding diagnosis at the 

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end of the study. This panel will be comprised of investigators Luchsinger, Goldberg, and Devanand. 
During the meeting, information of all the cognitive, functional and other clinical information of the 
participants will be presented, blind to study allocation. Evidence of cognitive deficits (based on the 
neuropsychological scores), evidence of impairment in social or occupational function (as assessed by the 
functional measures), and evidence of cognitive and social-occupational function decline will be the 
criteria used for the diagnosis of dementia. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
General questionnaires. We will collect demographic data including date of birth, sex, education, ethnic 
and racial group, and country of origin.144 We will measure depressive symptoms with the Geriatric 
Depression Scale145. Medical history (e.g., diabetes) and medications will be collected with questionnaires 
we currently use for other studies. 
COVID-19 questionnaire. The questionnaire includes questions about history of COVID-19, positive testing 
for coronavirus, symptoms and sequelae including memory problems, reinfection, and vaccination. A 
history of COVID-19 will be examined as a covariate and modifier.  
Laboratory tests. All laboratory tests will be conducted under fasting conditions. Screening (BMP, HbA1c, 
lipids, hepatic profile, CBC, RPR, B12 levels, TSH) will be conducted at the central laboratory at the Center 
for Advanced Laboratory Medicine (CALM) at Columbia. BMP, HbA1c, hepatic profile, lipids, B12 levels, 
and CBC will be repeated at each visit for safety purposes. TSH and RPR will not be repeated at the follow-
up visits. APOE will be genotyped (ε2, ε3, and ε4 alleles) by LGC genomics (Beverly, MA; 
http://www.lgcgroup.com) using single nucleotide polymorphisms (SNPs) rs429358 and rs7412.  APOE-ε4 
will be examined as a covariate and potential modifier. At the end of the study, we will conduct the 
following laboratory tests in stored samples to examine the impact of the intervention on intermediate 
outcomes:  Insulin levels will be measured using a solid-phase chemiluminescent enzyme immunoassay 
(Immulite, Diagnostic Products Co, Los Angeles, CA). Inflammatory markers will include hsCRP, serum 
Amyloid A, IL-6, IL-8, IL-1B, TNFa, WBC, MCP-1 will be measured using ELISA (Diagnostic Systems 
Laboratories, Inc., Webster, Texas). We will use the American Diabetes Association criteria for HbA1c to 
diagnose diabetes (HbA1c 6.5% or greater).146 We will calculate the homeostatic model assessment 
(HOMA)147 using glucose (from the BMP) and insulin values as a measure of insulin resistance.  
Adverse events.  Gastrointestinal symptoms and development of contraindications to metformin will be 
queried. Reported symptoms will be further evaluated for severity and duration until they resolve. SAEs 
will be collected and reported on SAE CRF pages.  
Measures used for screening. The Clinical Dementia Rating sum of boxes (CDR/CDRsob)148 will be used 
primarily for aMCI inclusion criteria but will be assessed at every visit. The Logical Memory II subscale 
from the Wechsler Memory Scale-Revised will be used for establishing early and late MCI criteria.149 The 
MMSE will also be used to establish entry criteria. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse events 
Adverse event (AE) means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention related. An AE can therefore be any undesirable sign, 

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symptom or medical condition occurring after starting IP, even if the event is not considered to be related 
to the pharmaceutical product. An AE can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, or dose, including 
an overdose (21 CFR 312.32 (a)). Headache, dizziness, lightheadedness, and gastrointestinal upset are 
AEs that will be specifically questioned about during phone calls and study visits. 
  
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An AE is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes:  
• 
Death 
• 
A life-threatening adverse event that places the participant at immediate risk of death at the time of 
the event as it occurred. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. This determination is based on the opinion of either the investigator or 
sponsor.   
The following hospitalizations are not considered SAEs:  
• 
Visits to the emergency room or other hospital department lasting less than 24 hours that do not 
result in admission (unless considered an “important medical event” or a life-threatening event); 
• 
Elective surgery planned before or after signing consent; 
• 
Medical/surgical admissions other than remedying ill health state that were planned before study 
entry. Appropriate documentation is required in these cases; 
• 
Admissions encountered for another life circumstance that have no bearing on health status and 
require no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason). 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.4 Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious”. 

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8.3.3.5 Relationship to Study Intervention 
All AEs must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect.  
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and follows a clinically reasonable response on withdrawal. 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the study intervention) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician.] 
8.3.3.6 Expectedness  
The study investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention, such as that described 
in the medication package insert. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Participants will have assessments including phlebotomy for safety laboratory every 6 months including 
baseline, 6-months, 12-months, and 18-months visits. In addition, participants will have monthly calls for 
monitoring of adverse events between visits.  The safety laboratory tests will include complete blood 
count, basic metabolic panel, hepatic panel, and vitamin B12 (cobalamin).  Cobalamin testing will allow to 
assess whether participants develop cobalamin deficiency and anemia, which could be due to metformin, 
or contraindications to metformin use such as hepatic insufficiency and severe renal insufficiency.  
At each study visit, the investigator will inquire about the occurrence of AE and SAEs since the last visit. 
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will be documented appropriately regardless of relationship. All AEs and SAEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded on the appropriate eCRF (e.g., AE or SAE). 
Changes in the severity of an AE or SAE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs and SAEs characterized as intermittent require 
documentation of onset and duration of each episode. 
8.3.5 ADVERSE EVENT REPORTING  
The site investigator is responsible for monitoring the safety of participants enrolled into the study. If an 
adverse event necessitates modification of study drug dosing, this will be captured on the Dose Change 
Log eCRF.  
All AEs and SAEs occurring from the first day of study enrollment (the day of randomization) to 30 days 
post last day of study drug dosing will be captured in the AE and SAE eCRF. Unless exempted as described 
in section 8.3.2, all SAEs, whether or not deemed drug-related or expected, must be reported to the CCC 
by the investigator or qualified designee within 24 hours of first becoming aware of the event. The 
investigator or qualified designee will enter the required information regarding the SAE into the 
appropriate module of the eCRF, which will automatically result in distribution of the information to the 
site-monitoring group, the Safety Event Adjudication Committee, and EMD Serono.  
Pregnancy and cancer are not always serious by regulatory definition; however, these events must be 
submitted to the sponsor within the same time period as an SAE via the EDC. 
If the eCRF system is temporarily unavailable, the event, including the investigator-determined causality 
to study drug should be reported via the back-up paper SAE form to Safety Surveillance. Upon return of 
the availability of the electronic data capture (EDC) system, the SAE information must be entered onto 
the eCRF. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the sponsor any SAE, whether or not considered study 
intervention related, including those listed in the protocol or investigator brochure and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event. 
Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between the study intervention 
and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the 
event to the sponsor. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the participant is stable. Other supporting documentation of the event may be requested by 
the DCC/study sponsor and should be provided as soon as possible. 
The study sponsor will be responsible for notifying the FDA, IRB and DSMB of any suspected, (possibly, 
probably, definitely related) unexpected serious adverse reaction (SUSAR) as soon as possible, but in no 
case later than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the 
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report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case 
later than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
We anticipate the following types of reports of events to participants:  
• 
Reporting of results of safety laboratory tests: All participants will receive written full reports of the 
complete blood count, basic metabolic panel, hepatic panel, and cobalamin level. These reports will 
indicate the normal levels for each value and will encourage participants to call the site PIs with any 
questions and/or consult with their primary care physicians. If abnormalities in these laboratory tests 
are deemed to be due to the study intervention, or constitute a new contraindication to the study 
intervention, participants will be informed by the site PI by telephone, and in writing.  
• 
Reporting of incidental findings in brain MRI. As indicated in section 2.3.3, there are 4 levels of 
incidental findings on MRI; level 3 requires non-urgent follow-up, and level 4 requires emergency 
follow-up. Site PIs will receive neuroradiology safety reads of the MRI within 72 hours. If level 3 
findings are reported, the site PI will contact the participants via telephone, and with the permission 
of the participant, their medical provider, in order to inform of the incidental finding. In addition, a 
written report of the incidental finding will be mailed to the participant and medical provider. For 
level 4 incidental findings, the participant will be contacted on an urgent basis with the instruction to 
present to an emergency room or urgent care provider immediately. 
• 
Reporting of new adverse events in our study, other studies, or the medical literature. In consultation 
with the DSMB and sIRB, we will compose a letter explaining the appearance of new information on 
the study drug reported in medical journals, other studies, and our study. This information will also 
be added to the consent form and participants will be re-consented at the next available visit.  
8.3.8 EVENTS REQUIRING A CHANGE IN IP DOSING  
At each study visit, the investigator will inquire about the occurrence of events that require a change in IP 
dosing, which may include, but are not limited to, hospitalizations, surgeries, and procedures that require 
holding metformin. Clinical events such as the development of anemia and/or B12 deficiency, and the 
development of contraindications to metformin, such as New York Heart Association Class III or IV 
congestive heart failure, and renal or hepatic insufficiency deemed to be of clinical significance are other 
examples of events that may require a change in IP dosing. Changes in IP dosing, and the associated 
reason, will be captured on relevant eCRF pages. Events above pre-specified thresholds as outlined in the 
Data Safety Monitoring Plan will trigger a review by the DSMB to investigate the presumed cause and 
impact of these events. Such events are initially reviewed by a Data Coordinating Center (DCC) staff 
member to determine if an event threshold has been reached, at which time the study investigators and 
the DSMB will be notified. 
8.3.9 REPORTING OF PREGNANCY  
Although our cohort will be between the ages of 55 and 90 years, there is the possibility of pregnancy.  If, 
following initiation of the IP, it is subsequently discovered that a study participant is pregnant or may have 
been pregnant at the time of IP exposure, the IP will be permanently discontinued. 
The Investigator must immediately notify the PI and the Safety Event Adjudication Committee of this 
event within 24 hours and in accordance with SAE reporting procedures. 

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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
must be reported. Any associated AEs or SAEs that occur to the mother or fetus/child will be recorded in 
the SAE CRFs.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant unless contraindicated by pregnancy.  
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the single IRB (sIRB)-approved research 
protocol and informed consent document; and (b) the characteristics of the participant population 
being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing sIRB and to the DCC/lead 
principal investigator (PI). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents a UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
Unanticipated problems that are SAEs will be reported to the DCC/study sponsor within 24 hours of 
the investigator becoming aware of the event, and a determination will be made in regard to their 
relation to the study drug. Those SAEs considered to be related to the study drug will be reported to 
the sIRB within 7 days of occurrence. Those SAEs not related to the study drug will be reported to the 
sIRB in annual reports.  SAEs considered related to the study drug will be reported to the IRB and to 
the within 7 days.  
• 
Any other UP will be reported to the DCC/study sponsor within 48 hours of the investigator becoming 
aware of the problem and will be reported to the sIRB annually.   
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s written 
reporting procedures), the supporting agency head (or designee), and the Office for Human Research 

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Protections (OHRP) within 7 days of the sIRB’s receipt of the report of the problem from the 
investigator. 
• 
For more information on sIRB reporting requirements, The JHM IRB Organizational Policy on Prompt 
Reporting of Reportable Events can be referenced here: 
https://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/organization_po
licies/prompt_reporting_policy.html 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
If UPs possibly, probably, or definitely related to the study drug appear in the literature, other studies, or 
this study, which could change the risk of the study participation, the investigators will draft a letter to all 
participants describing this new information, the likelihood that it is related to the study drug, how this 
information alters the risk to participate in the study, and new measures taken to ensure the safety of 
participants. This process will be done with review and approval of the sIRB and DSMB. In addition, this 
new information will be added to the consent form and study participants already enrolled will be re-
consented.  
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
Primary efficacy endpoint(s) 
The primary aim is to compare changes from baseline to 18 months in verbal memory performance, 
measured with the Total Recall Score of the Free and Cued Selective Reminding Test (FC-SRT), between 
the metformin and placebo arms, following an ITT approach. We hypothesize that the metformin arm will 
demonstrate less decline in the FC-SRT as compared with placebo. 
Secondary efficacy endpoint(s):  
• 
Examine global cognitive performance, measured with the Alzheimer’s Disease Cooperative Study, 
Preclinical Alzheimer Cognitive Composite (ADCS-PACC). We hypothesize that the metformin arm will 
demonstrate less decline or improvement in the ADCS PACC as compared with placebo.  
• 
Examine APOE-ε4 genotype as a modifier of the efficacy of metformin. We hypothesize that the 
benefit of metformin will be highest among APOE-ε4 carriers. 
• 
Compare changes in neurodegeneration, ascertained as cortical thickness in areas affected by 
Alzheimer’s disease acquired on brain MRI from baseline to 18 months between metformin and 
placebo. We hypothesize that the metformin arm will show less decrease in cortical thickness at 18 
months compared with placebo.  
• 
Compare changes in cerebrovascular disease, ascertained as white matter hyperintensities (WMH) 
volume on brain MRI, from baseline to 18 months between metformin and placebo. We hypothesize 
that the metformin arm will show less increase in WMH as compared with the placebo arm. 
• 
Compare changes in whole brain Aβ standardized uptake value ratio (SUVR) and in incident amyloid 
positivity from baseline to 18 months between the metformin and placebo arms. 
• 
Compare changes in tau SUVR in a composite brain region comprising medial and inferolateral 
temporal cortex from baseline to 18 months between the metformin and placebo arms.  
• 
Compare changes in plasma AD biomarkers between metformin and placebo.  

M etf or mi n i n Alz h ei m er’s d e m e nti a Pr ev e nti o n ( M A P)  
V ersi o n 2. 0  
Pr ot oc ol N C T 0 4 0 9 8 6 6 6  
2 1 M a y  2 0 2 4  
 
5 0  
 
9. 2  
S A M P L E SI Z E D E T E R MI N A TI O N  
9. 2. 1. Ori gi n al S a m pl e siz e c alc ul ati o n. S a m pl e siz e h as b e e n c alc ul at e d f or t h e diff er e nc e i n av er a g e 
c h a n g e i n S R T sc or es at 2 4 m o nt hs fr o m b as eli n e b et w e e n m etf or mi n a n d pl ac e b o ar ms. I n t h e pr evi o us 
st u dy, M et M CI, a v er a g e c h a n g e i n S R T sc or e at 1 2 m o nt hs a m o n g m etf or mi n s u bj ects w as 9. 8 ( S D = 8. 6) 
v ers us 5. 9 ( S D = 8. 5) i n t h e pl ac e b o ar m, w hic h c orr es p o n ds t o a st a n d ar diz e d diff er e nc e i n m e a ns 
m e as ur e d as C o h e n’s D of 0. 4 6 ( 9 0 % CI: 0. 0 6 t o 0. 8 6). I n t h e pl ac e b o ar m, av er a g e c h a n g e i n S R T w as 
si mil ar at 1 2 m o nt hs a n d 9 m o nt hs. H o w e ver, i n t h e m etf or mi n ar m, av er a g e S R T c o nti n u e d t o i m pr o v e 
fr o m 9 t o 1 2 m o nt hs. T h es e d at a ar e b as e d o n 3 3 ( 8 2. 5 %) vs. 3 7 ( 9 2. 5 %) s u bj ects wit h n o n -missi n g 
o utc o m e d at a at 1 2 m o nt hs i n m etf or mi n a n d pl ac e b o ar ms, r es p ectiv ely. Ass u mi n g t h at a si mil ar 
st a n dar diz e d diff er e nc e i n m e a ns will b e o bs er v e d at 2 4 m o nt hs, o ur c alc ul ati o n i n dic at es t h at w e will 
n e e d 8 7 p artici p a nt s p er ar m t o d et ect t his eff ect siz e wit h 9 0 % p o w er, r ej ecti n g t h e n ull hy p ot h esis at 
0. 0 8 l e v el of st atistic al si g nific a nc e. T his o bs er v e d st a n d ar diz e d diff er e nc e c orr es p o n ds t o a “ m e di u m” 
eff ect siz e ( C o h e n, 1 9 8 8). If, h o w ev er, t h e o bs er v e d diff er e nc e at 2 4 m o nt hs c orr es p o n ds t o l o w -t o-
m e di u m eff ect siz es (i. e. , C o h e n’s D b et w e e n 0. 3 5 a n d 0. 4), t h e r e q uir e d m axi m u m s a m pl e siz e is 3 0 2.  T h e 
sel ect e d t ot al s a m pl e siz e of 3 7 0 p artici p a nts  will b e a d e q u at e t o d et ect eff ect siz es 0. 3 5 a n d l ar g er, 
ass u mi n g ov er all dr o p -o ut/ missi n g n ess of a b o ut 2 0 %. Si nc e t h e o nl y diff er e nc e b et w e e n tr e at m e nt ar ms 
w as o bs erv e d i n A P O E e 4 n e g ati v e p artici p a nt s, w e p erf or m e d s a m pl e siz e c alc ul ati o ns f or t his s u b gr o u p. 
T h e o bs erv e d st a n d ar diz e d diff er e nc e i n a v er a g e c h a n g e i n S R T sc or e b et w e e n m etf or mi n a n d pl ac e b o at 
1 2 m o nt hs w as 0. 6 , ( 9 0% CI: 0. 1 3 t o 1. 0 7). Wit h a s a m pl e siz e of 3 0 2 ( or a dj ust e d f or missi n g at 3 7 0) a n d  
ass u mi n g 6 0 % p artici p a nt s will b e A P O E e 4 n e g ati v e, w e will h a v e 9 0 % st atistic al p o w er t o d et ect t his 
eff ect siz e or l ar g er by r ej ecti n g t h e n ull hy p ot h esis at 0. 0 1 l ev el of st atistic al si g nific a nc e.  
 
9 . 2. 2. N e w s a m pl e siz e c alc ul ati o n f or pr ot oc ol v ersi o n 1. 9 . T h e s a m pl e siz e is c alc ul at e d b as e d o n t h e 
d at a o bs erv e d i n p h as e II tri al of m etf or mi n i n a M CI ( M et M CI) t h at f oll o w e d 8 0 p ati e nts ( 4 0 p er ar m) wit h 
l at e a M CI u p t o 1 2 m o nt hs. I n or d er t o d et er mi n e t h e s a m pl e siz e of f or t h e p h as e II/III st u dy, t h e TI C t e a m 
c alc ul at e d t h e m e a n c h a n g es fr o m b as eli n e t o all f oll o w -u p ti m e p oi nts i n t ot al r ec all of t h e S el ect e d 
R e mi n di n g T est ( S R T) fr o m t h e M et M CI pil ot st u dy a n d esti m at e d t h e s a m pl e siz es n e c ess ary t o fi n d 
st atistic al si g nific a nc e f or t h e diff er e nc es b et w e e n st u dy ar ms at e ac h ti m e p oi nt, ass u mi n g = 0. 2 ( 8 0 % 
p o w er) a n d  = 0 . 1. T h e o bs er v e d eff ect siz es ( C o h e n’s D)1 r a n g e d b et w e e n a mi ni m u m of 0. 2 1 f or t h e 
m o nt h 9 diff er e nc e t o 0. 5 2 f or t h e m o nt h 6 diff er e nc e. Cli nic al tri als of i nt er v e nti o ns t o pr ev e nt c o g nitiv e 
d ecli n e h av e yi el d e d s m all eff ect siz es ( e. g. 0. 1 C o h e n D) t h at ar e of d u bi o us cli nic al si g nific a nc e. A C o h e n 
D of 0. 5 ( m o d er at e eff ect siz e) is us u all y c o nsi d er e d cli nic all y si g nific a nt, b ut u nli k el y t o b e ac hi e v e d i n a 
cli nic al tri al of i nt er v e nti o ns t o pr e v e nt c o g nitiv e d ecli n e. T h us, w e s ettl e d o n a s m all t o m o d er at e t ar g et 
eff ect siz e ( 0. 3 C o h e n D).  F or  a n eff ect siz e  of  0. 3  C o h e n D  t h e c alc ul at e d s a m pl e siz e is 2 7 8 f or t h e p h as e 
II/III st u dy. C o nsi d eri n g a p ot e nti al a n n u al l oss of f oll o w-u p of a b o ut 1 0 %, t h e fi n al s a m pl e siz e t o 3 2 6 . Is 
i m p ort a nt t o p oi nt o ut t h at gi v en t h e pr o p os e d a n al ytic a p pr o ac h, t h e st u dy is p o w er e d t o d et ect s m all er 
diff er e nc es.  We ass ess e d t h e st atistic al p o w er  f or t h e pr o p os e d st u dy b as e d o n diff er e nc es i n t h e sl o p es 
or tr e n ds b et w e e n tr e at m e nt ar ms i n t h e S R T ov er 1 2 m o nt hs (i. e. a d diti o n al a n al ysis f or t h e pri m ar y 
o utc o m e). A r e gr essi o n m o d el wit h r o b ust  st a n d ar d err ors t o  acc o u nt  f or wit hi n p ers o n cl ust eri n g  
p erf or m e d o n t h es e pr eli mi n ar y d at a, r ev e al e d a n S R T sl o p e ( 9 5 % CI) of 0. 8 4 ( 0. 5 6, 1. 1 3) p oi nts / m o nt h 
i n t h e m etf or mi n gr o u p, a n S R T sl o p e ( 9 5 % CI) of 0. 5 2 ( 0. 2 5, 0. 7 9) p oi nts / m o nt h a m o n g t h e pl ac e b o 
p ati e nts, a n d a diff er e nc e i n sl o p es ( e. g. i nt er act i o n) of -0. 3 3 p oi nts / m o nt h ( p = 0. 1 0). Si m ul ati o ns w er e 
p erf or m e d o n r e plic at es of t h es e d at a, usi n g t h e tr e at m e nt by ti m e i nt er acti o n i n r e gr essi o n a n al ysis.  
B as e d o n o ur s a m pl e siz e c alc ul ati o n, o n e h u n dr e d -fift y ( 1 5 0) p ati e nts w er e r a n d o mly c h os e n fr o m e ac h 
tr e at m e nt ar m i n t h e r e plic at e d d at a, a n d t h e r e gr essi o n m o d el p erf or m e d o n e ac h of 1 0, 0 0 0 si m ul at e d 
s a m pl es. A n ot h er 1 0, 0 0 0 s a m pl es w er e als o cr e at e d t o esti m at e t h e p o w er of t h e tr e at m e nt eff ect o n 

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only ApoE-ε4 negative patients. The power for the overall sample was based on a type I error of 0.08, 
while a type I error rate of 0.01 was used for the ApoE-ε4 negative participants. An additional alpha of 
0.01 was allocated for the ApoE-ε4 positive patients; however, simulations were not undertaken for this 
patient population, since there was no preliminary evidence of a treatment effect among the ApoE-ε4 
positive patients. Based on these data simulations, we estimate a power of 92.4% to statistically detect a 
larger FC-SRT slope in the metformin group as compared to the FC-SRT slope among the placebo arm (e.g. 
9240 out of 10,000 samples produced a significant interaction model term at the alpha = 0.08 level in the 
regression analysis). Similarly, we found an estimated power of 97.8% to detect a statistically larger FC-
SRT slope in the metformin versus placebo groups among the ApoE-ε4 negative patients at alpha = 0.01 
level. The proportion of ApoE-ε4 negative patients ranged from 67% to 79% among the 10,000 simulated 
samples, as compared to a proportion of 73.8% for the ApoE-ε4 negative patients (59 of 80) in the 
preliminary study.  
Given these power analyses, the study team is confident that the reduction in sample size from 370 to 
326 will not compromise the goals of the study.  
9.3 
POPULATIONS FOR ANALYSES 
The population for analyses will be all 326 randomized participants based on an intent to treat approach. 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Exploratory data analysis will be performed on the entire study sample. All variables will be checked for 
outlying and unusual observations to detect general patterns, identify gaps and inconsistencies in the 
data. Visual inspection will be performed by means of box plots, scatterplots, quantile plots and others. 
Outliers will be checked for possible data entry errors. Reported descriptive statistics for continuous 
variables will include the number of participants with non-missing observations, median, mean, SD, 
interquartile range and range, while statistics for categorical variables will include the frequency and 
percentage of participants in each category. 
Adjustment for covariates. In the primary analysis, all models described below will be adjusted for, ApoE-
ε4 (as a binary indicator), age (continuous), self-reported sex (male or female) (categorical), baseline total 
recall FC-SRT score (continuous), MMSE score (continuous), BMI (continuous) and HbA1c level. Additional 
adjustment for site, BMI, gender, race, educational attainment, COVID-19 history, and white matter hyper 
intensity will be done as sensitivity analyses.  Statistical tests will be two-sided.  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Analytic Plan for the Primary Aim. The primary aim for this study is to compare changes from baseline to 
18 months in verbal memory performance, measured with total recall in the FC-SRT, between the 
metformin and placebo arms. The primary null hypothesis H0 states that there is no difference between 
metformin and placebo arms on change in total recall in the FC-SRT from baseline to 18 months of follow-
up. We will follow the ITT principle in which all randomized participants are analyzed based on the group 
to which they are randomized regardless of early termination or errors in randomization detected post 
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To estimate the average treatment effect, we will use the targeted maximum likelihood estimator (TMLE) 
of van der Laan and Gruber (2012). This estimator involves adjustment for baseline (i.e., pre-
randomization) variables that are correlated with the outcome to improve precision in estimating the 
average treatment effect for FC-SRT score at 18 months. The estimator also involves adjustment aimed at 
reducing bias due to informative censoring, that is, participant dropout that may be correlated with the 
primary outcome. This adjustment for missing outcomes is done through a combination of inverse 
probability of censoring weights and outcome prediction models. Specifically, the weights and prediction 
models use the pre-specified baseline variables, study arm, and the post-randomization outcomes at 0, 6, 
12, and 18 months. The motivation of this approach is that if the FC-SRT score at a given visit is correlated 
with the FC-SRT value at the next visit and also with dropout, then adjusting for observed differences in 
FC-SRT scores for those who dropout versus those who stay on study may reduce bias (under the 
assumption that censoring is missing at random). This adjustment is implemented by fitting models for 
dropout as a binary outcome using logistic regression models for the primary outcome based on FC-SRT 
measured at the previous visit, study arm, and baseline variables. 
As the final step, average FC-SRT score under hypothetical assignment to the active treatment is estimated 
for each participant at 18 months (regardless of their actual assignment), given their baseline covariates. 
Similarly, average FC-SRT score under hypothetical assignment to the comparison arm is estimated. The 
primary analysis estimator of the average treatment effect as a mean difference is defined as the 
difference between the former and the latter. This analysis will be performed in a software that 
implements 
the 
above 
estimator: 
https://github.com/mrosenblum/RandomizedTrialEnhancedPrecisionEstimator. 
To test the null hypothesis that the average treatment effect equals 0, a Wald statistic will be computed 
that is equal to the estimator of the average treatment effect divided by its estimated standard error. The 
standard error will be computed by the non-parametric bootstrap (resampling participants with 
replacement and recomputing the above estimator), and the 92% confidence interval will be computed 
using the bias corrected (BC) and accelerated (BCa) method.  
Prior to computing the average treatment effect, missing baseline variables will be imputed using the 
median for continuous-valued variables (such as age and MMSE) and mode for categorical variables (such 
as site, APOE e4 status, gender, and education level). Intermittent missing outcomes at each time point 
will be imputed with fitted values from a regression model using all baseline covariates, previous 
outcomes, and treatment assignment as covariates.  
Subpopulation defined by APOE-ε4 genotype. The primary pre-specified subpopulation analysis is in terms 
of the APOE-ε4 genotype. Two subpopulations will be defined based on the genotype: 1) any APOE-ε4 
allele present, i.e.  APOE-ε4 positive and 2) no APOE-ε4 allele present, i.e., APOE-ε4 negative). For each of 
the two subgroups, the above-described estimator will be computed, and the null hypothesis of no 
difference will be tested at 0.01 level of significance. If any of the three (one for combined population, 
and one for each of the two subpopulations) primary null hypotheses are rejected at their respective 
significance levels, the decision will be made to proceed to a phase III trial. COVID-19 history will be 
explored as a potential modifier of the intervention.  
9.4.2.1 Additional efficacy analyses: longitudinal analysis of outcomes  
The following will be used as sensitivity analyses. 
Longitudinal analysis will examine the primary and secondary outcomes that are longitudinally collected 
at baseline and at 6, 12, and 18 months.  Linear mixed effect model will be used, with FC-SRT as the 
primary outcome and time (in months), treatment (binary indicator) and their interaction as the primary 

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predictors. The model will include site and APOE-ε4 as categorical covariates and random intercept for 
participant to account for within-person correlation of FC-SRT scores. As noted above, additional 
adjustments will be included for participant pre-randomization characteristics (such as age, gender, 
education level, baseline MMSE or others) that show clinically meaningful differences between treatment 
arms. This model will be further modified to 1) use time points as four indicator variables rather than a 
linear term (i.e., 6, 12, and 18 months vs. baseline), 2) include random slope for time as a linear term to 
account for potential heterogeneity in trajectories across participants. This model will estimate two 
random effect variances and their covariance, and 3) account for potential correlation of residuals by 
specifying a covariance structure for residuals. These additional models will be informed by exploratory 
analysis of outcome distribution over time and will be compared using Bayesian Information Criterion 
(BIC). Similar longitudinal analyses will be performed for secondary outcomes.  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Analytic plan for secondary aims. Our secondary aims compare changes in the ADCS-PACC between 
metformin and placebo on an ITT basis. The analytic approach will be the same as described for the 
Primary Aim. This will also apply to outcomes measured at all visits, including the plasma AD biomarkers.  
We will also compare changes from baseline to 18 months between metformin and placebo in brain 
cortical thickness, white matter hyperintensity volume, brain amyloid SUVR, and brain tau SUVR.  Since 
these analyses will have only 2 time points, we will use analysis of covariance to compare the mean 
changes from baseline to 18 months, adjusting for study site and other prespecified covariates in the 
primary analysis.  
9.4.4 SAFETY ANALYSES 
The number of SAEs will be tabulated by type for the entire study sample as well as by treatment group. 
Any treatment group differences in SAEs enumerated for interim analyses will remain blinded to 
investigators associated with this study. Unmasked results will be made available only during the closed 
sessions of DSMB meetings.  
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Treatment arms will be compared on pre-randomization (baseline) characteristics potentially correlated 
with outcomes to assess for differences in distributions and, therefore, potential confounding. No 
inferential statistics will be used. 
9.4.6 PLANNED INTERIM ANALYSES  
Safety data will be looked at by the DSMB at a specified schedule, which is different from a formal interim 
analysis for efficacy. There will be no interim analysis for efficacy. 
9.4.7 SUB-GROUP ANALYSES 
Analyses of primary and secondary outcomes will be stratified by the following baseline participant 
characteristics: (primary) APOE e4 status and age, gender, race, site, type of MCI (early vs. late), BMI, 
cognition and metabolic status, as measured by Hb1Ac. 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 

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No individual participant data will be tabulated. Individual level data might be presented to the DSMB in 
a closed report, at their specific request.  
9.4.9 EXPLORATORY ANALYSES 
Exploratory analyses will include: sensitivity analyses including and excluding data outliers for which data 
entry errors were ruled out: exploratory analyses examining different metformin cumulative doses 
according to the doses tolerated during the study; examination of other outcomes such as functional 
outcomes and other neuropsychological domains such as executive function. 
9.4.10 DECISION TO MOVE TO PHASE III TRIAL 
The advantage of phase II/III study design is that it is an adaptive design and can decrease the overall 
number of participants, time and cost of making the decision about efficacy of the intervention. The 
decision to move to a phase III trial will be based on the analysis of the unblinded phase II trial data, made 
by a data monitoring committee independent of the study investigators and the DSMB, and will include 
at least one biostatistician.  
Phase III will not be started until all phase II primary outcome data are analyzed. As noted above, if the 
primary hypothesis regarding the average treatment effect is rejected either for the entire sample or one 
of the primary subgroups based on the APOE e4 status, at their respective statistical significance levels, 
the decision will be made to proceed to the phase III trial.  
The decision about the participant eligibility/study population for phase III trial will be based on the 
average treatment effect in the entire study sample versus the primary subgroups. If a positive treatment 
effect is observed (i.e., average treatment effect > 0 comparing metformin vs. placebo arm) in the study, 
no additional exclusions for phase III compared to phase II study population will be implemented. 
However, this decision might be modified by the independent committee depending on the safety profile 
among different participant subgroups.  
Statistically, the phase II and phase III trials are distinct, i.e., no phase II data will be used in the primary 
analysis of the phase III trial. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
10.1.1.1 Overview 
The investigator is responsible for following all federal, state, and local regulations regarding the 
obtainment of informed consent from all participants (e.g., 21 CFR 50). The investigator or designee must 
explain to each participant (or legally authorized representative) the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any discomfort 
it may entail. Each participant must be informed that participation in the study is voluntary and that 
he/she may withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 

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The ICFs must be submitted by the investigator for sIRB/IEC approval. The CCC will supply template ICFs 
that comply with regulatory requirements and are appropriate for the study.  
10.1.1.2 Consent Procedures and Documentation 
Informed consent will be conducted in person, electronically, or remotely by video or telephone using a 
hard-copy (paper) ICF. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be IRB-approved and 
the participant will be asked to read and review the document. The consent designee will explain the 
research study to the participant and answer any questions that may arise. A verbal explanation will be 
provided in terms suited to the participant’s comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants should have 
the opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. Participants must be informed that participation is voluntary and that they may withdraw 
from the study at any time, without prejudice. A copy of the signed ICF will be given to the participants 
for their records. The informed consent process must be conducted, and the form signed, before the 
participant undergoes any study-specific procedures. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study.  
MAP requires the participation of a study partner who should be available by telephone or in person to 
answer questionnaires about the participant’s cognition, mental health, and function. The study partner 
must provide verbal consent to participation. The consent designee will read a consent script and 
document that the study partner verbally consented to participation in the MAP trial. The waiver of 
written documentation of consent is available only to study partners, not to study participants.  
Electronic consent procedure: to conduct informed consent electronically, the consent designee will 
perform the informed consent process as stated above but will utilize the VISION EDC instead of a paper 
consent form. First, the consent designee will walk the participant through creating a personal account in 
VISION. In their new VISION account, the participant will be taken to the electronic informed consent form 
(eICF), either in English or Spanish based on their preferred language and will have the opportunity to 
carefully review the electronic consent form and ask questions prior to signing. The participants should 
have the opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate, as with an in-person consent. After reviewing the document in the desired language, the 
participant will answer the questions in the consent form, sign and date the consent form, and save the 
form by using VISION’s eICF functions. A link to the signed eICF will then be provided to the participant so 
they can access it to print or review at any time. Lastly, the VISION database will store and track audit 
trails for initial and re-consents. 
Remote paper consent procedure: a copy of the IRB-approved ICF is provided to the participant prior to 
the remote consent meeting via email, fax, or mail. The consenting process may be conducted either via 
telephone or video. After the participant reviews the consent form, he/she is offered the opportunity to 
ask any questions and have those questions answered. The consent designee must verify the participant 
physically signed the ICF either by viewing this via video conference, obtaining a photo of the signed pages 
from the ICF, or obtaining verbal confirmation from the participant that he/she signed the consent form. 
The consent designee will sign their ICF copy after the participant has acknowledged signature on their 
copy. The signed pages of the ICF (optional components of the study (future contact, future use of 
biospecimens, undergoing MRI) and the site-specific section of the consent)) are then mailed, emailed, 

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photo/scanned to text, or faxed to the consent designee. Once the consent designee receives the signed 
pages of the ICF, as an electronic copy (emailed, photo/scanned to text, or faxed), or by mail, study-
specific procedures may be commenced. The participant must return the original signed document on 
their first in-person visit. Once the participant’s original copy is received, the consent designee will append 
this to their own signed copy and create a single document. No study-related procedures may occur until 
the consent designee is in possession of the signed ICF. 
There will be three informed consent forms, one for the main study, one for the PET imaging sub-study, 
and one for volunteers (non-participants) undergoing MRI for calibration.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to the investigator. If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the sIRB, and sponsor 
and will provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
• 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or FDA. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, regulatory 
agencies or pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, clinic, 
or hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 

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Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Johns Hopkins TIC DCC. This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by clinical 
sites and by the Johns Hopkins TIC DCC research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the Johns Hopkins TIC DCC. 
Certificate of Confidentiality (if applicable) 
To further protect the privacy of study participants, a Certificate of Confidentiality (CoC) will be issued by 
the NIH.  This certificate protects identifiable research information from forced disclosure. It allows the 
investigator and others who have access to research records to refuse to disclose identifying information 
on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at 
the federal, state, or local level. By protecting researchers and institutions from being compelled to 
disclose information that would identify research participants, (CoCs) help achieve the research objectives 
and promote participation in studies by helping assure confidentiality and privacy to participants. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the Johns Hopkins TIC DCC. After the study is 
completed, the de-identified, archived data will be transmitted to and stored in a NIH-approved public 
data repository (to be determined), for use by other researchers including those outside of the study. 
Permission to transmit data to the public Data Repository will be included in the informed consent.  
With the participant’s approval and as approved by local IRBs, de-identified biological samples will be 
stored at the CUMC Biospecimen Repository with the same goal as the sharing of data with the public 
data repository. These samples could be used to research the causes of Alzheimer’s disease, its 
complications and other conditions for which individuals with Alzheimer’s disease are at increased risk, 
and to improve treatment. The CUMC Biospecimen Repository will also be provided with a code-link that 
will allow linking the biological specimens with the phenotypic data from each participant, maintaining 
the blinding of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to bio-
sample storage may not be possible after the study is completed.  
When the study is completed, access to study data and/or samples will be provided through the CUMC 
Biospecimen Repository. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
11.1.5.1 Overall Structure of the Study Team 
The following is a description of the elements of the study team:   
Principal Investigator:  José Luchsinger, MD, MPH 
 
 
 
Columbia University Irving Medical Center 
 
 
 
630 West 168th Street, 
 
 
 
New York, NY 10032 
Medical Monitor:  
Natasha Mehta, MD, address as above 

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Administrative center based at CUMC. The center is led by Dr. Luchsinger who will be assisted by a full-
time program manager responsible for the logistics of coordinating and communicating with all study 
components and clinical sites. Dr. Luchsinger will be responsible for all contacts with the funding agency, 
NIA.  
Clinical coordinating and monitoring center (CCMC) based at CUMC. The CCMC will be led by Drs. 
Luchsinger and Terry Goldberg, who will be assisted by a senior coordinator. The CCMC will oversee QA 
and quality control (QC) related to the collection of the non-brain imaging data. The CCMC will organize 
remote training and certification in study procedures and will conduct QC procedures including double 
scoring of all neuropsychological tests and yearly site visits as needed. The PI will designate a medical 
monitor who will monitor adverse events in coordination with the CCMC and the clinical sites. 
Data coordinating center (DCC) based at the John Hopkins TIC, led by Daniel Hanley, MD, Professor of 
Neurology, assisted by Lindsay M Eyzaguirre, MS, Project Administrator, Ying Wang, MS, Senior Research 
Data Analyst and Gayane Yenokyan, PhD, Associate Scientist, Biostatistics Consulting Center. The DCC will 
assist the CCMC in QC activities and will oversee QA/QC related to data upload and management. The 
DCC will also lead the randomization process. 
Single IRB will be the Johns Hopkins Medicine IRB (JHM sIRB). 
Imaging core will be located at the Johns Hopkins TIC, led by Dr. Hanley. The Imaging Core will oversee all 
QA/QC procedures related to acquisition, transfer, processing, and analysis of brain MRI images. The 
Imaging Core will conduct site visits in Year 1 of the study in order to harmonize image acquisition across 
sites.  
PET core will be located at the University of California-Berkeley, led by William Jagust, MD. 
Central research pharmacy function will be shared by the research pharmacies of the University of 
Rochester and University of Iowa. The University of Iowa will bottle IP received in bulk from the EMD 
Serono Research & Development Institute, and will send it to the University of Rochester, which will 
prepare kits for dispensation to clinical sites in coordination with the DCC, who will lead the randomization 
process.  
Central laboratory function will be located at CALM at CUMC, led by Eldad Hod. CALM will prepare kits 
for all study sites with laboratory supplies per participant and a return package, send the kits to the clinical 
sites, receive them within 24 hours, process the samples and conduct laboratory assays, and return the 
results to the CCMC.  
Data safety and monitoring board (DSMB) has four members: Anton Porsteinsson, MD (chair), Professor 
of Psychiatry at the University of Rochester, expert in Alzheimer’s clinical trials;  Steven Arnold, MD, 
Professor of Neurology at Harvard Medical school, expert in Alzheimer’s disease with experience in 
metformin trials; Jonathan Purnell, MD, Professor of Medicine at Oregon Health and Science University, 
endocrinologist with expertise in metformin; Emilia Bagiella, PhD, Professor of Population Health Science 
and Policy at Mount Sinai, a statistician with expertise in clinical trials. The DCC will provide reports to the 
DSMB as needed. The DSMB will hold meetings or calls twice a year.  
The previous elements will be coordinated by an executive committee that will hold weekly one-hour calls 
or convene as needed in case of contingencies. The executive committee will be led by José Luchsinger 
and will include Drs. Terry Goldberg, Devangere Devanand, and Daniel Hanley, representatives of the 
Johns Hopkins TIC, and three members from the clinical sites outside of CUMC. The executive committee 
will be charge of resolving any conflicts or contingencies, such as underperforming clinical sites. The 
executive committee and all the clinical site PIs and coordinators will convene once a year at a central 
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10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a DSMB. Members of the DSMB should be independent 
from the study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest.  The DSMB will meet at least semiannually to assess safety and efficacy data 
on each arm of the study. The DSMB will operate under the rules of an approved charter that will be 
written and reviewed at the organizational meeting of the DSMB. At this time, each data element that the 
DSMB needs to assess will be clearly defined. The DSMB will provide its input to CUMC, Johns Hopkins TIC 
Data Coordinating Center, and NIH staff. 
The DSMB will be responsible for the interests of the participants and, to this end, will undertake regular 
reviews of the safety data. The DSMB will have access to all study data throughout the study duration.  If 
the DSMB finds it necessary to recommend actions regarding interruption of the study or changes to the 
protocol based on medical rationale that would make it unethical to continue the study in its present 
form, those recommendations will be forwarded to the sponsor who will then take appropriate action.  
The sponsor will make any changes, protocol amendments, etc. necessary to meet the recommendations 
of the DSMB. The sponsor will then propagate those changes to the site PI’s and others as necessary.  
Details of the DSMB's functions and early stopping rules will be delineated in a separate DSMB charter. 
The study may be stopped at any time if, in the opinion of the Sponsor, the Medical Monitor, or the DSMB, 
continuation of the study represents a serious medical risk to the participants. This may include, but is not 
limited to, the presence of serious, life threatening, or fatal AEs, or AEs that are unacceptable in nature, 
severity, or frequency. 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with applicable regulatory 
requirement(s).  
• 
The CCC located at Columbia University Irving Medical Center will provide centralized monitoring, 
throughout the study, and targeted data verification of endpoint, safety and other key data variables, 
and the distribution of monitoring reports. 
• 
Independent audits will be conducted by the CCC located at Columbia University Irving Medical 
Center to ensure monitoring practices are performed consistently across all participating sites. 
• 
The frequency of site contact will be monthly for routine monitoring.  Monitoring will take place 
weekly while the site is under enhanced monitoring.   
Central monitoring: site and project metrics will be compiled and reviewed routinely with the study sites 
and formally reviewed by the Columbia University Irving Medical Center monitoring team.  Appropriate 
documentation will be retained in the electronic Trial Master File (eTMF), to include the findings of the 
review, whether any thresholds have been breached, and any action items to be addressed.   
Site Management: As one of the “monitoring checks,” a site manager will routinely communicate with 
sites via weekly project meeting and Study Coordinator calls biweekly.  The monitor should make a 
qualitative assessment of the risk-level for the site and note new risk issues in the eTMF.  If the site 
manager or monitor has material concerns about any aspect of site performance, he or she should 
escalate the site to enhanced monitoring until those concerns are addressed.   

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Source Document Verification (SDV): Sites will be required to enter data promptly with the participant’s 
completed informed consent with 48 hours; all other data should be entered within 7 days of the visit and 
to upload associated source documents. (Note: Generally, the EDC will be the primary/original source of 
most study data (no source to review), albeit worksheets will be provided for critical assessments and 
medical history may be taken from clinic charts.) Monitors will review the EDC entries against the available 
source documents within 15 days of upload and generate associated queries. Sites are expected to resolve 
queries within 15 days. A site’s failure to enter data, upload source documents or answer queries promptly 
is a risk-elevation issue that, if not promptly resolved, should trigger enhanced monitoring. The baseline 
percentage (approximate) of SDV review is stipulated as: 
• 
CRF entries vs. source documents supporting critical data & processes: ≥ 80% 
• 
Informed Consents (properly executed): 25% 
• 
CRF entries vs. source documents on other data: 25% 
The Johns Hopkins TIC Data Coordinating Center will develop a set of data verifications that will be run in 
off-line mode for the purposes of data cleaning, as stipulated in the Data Management Plan.  Johns 
Hopkins TIC Data Coordinating Center will review the EDC entries for completeness, timeliness, 
compliance with the protocol and general accuracy with expected medical practice.  Critical Data and 
Processes will be reviewed at a higher percentage than other data.  Critical Data Points include: 
• 
Age 
• 
Gender 
• 
BMI 
• 
Documentation of the Total Recall Score of the Free and Cued Selective Reminding Test (FC-SRT) 
• 
Documentation of the Alzheimer’s Disease Cooperative Study, Preclinical Alzheimer Cognitive 
Composite Score (ADCS-PACC) 
• 
In those participants who underwent MRI, upload of MRI Images at baseline and 18 months 
• 
APOE-ε4 genotype 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation, and completion.  An individualized quality management plan will be developed 
to describe a site’s quality management.] 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written standard operating procedures (SOPs), the monitors will verify that the clinical trial is 
conducted, data are generated, and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  

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10.1.9.1 Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
Clinical data (including AEs and concomitant medications) and clinical laboratory data will be entered into 
Prelude Dynamics VISION, a 21 CFR Part 11-compliant data capture system provided by the Johns Hopkins 
TIC Data Coordinating Center. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents. 
Responsibilities of the Johns Hopkins TIC data coordinating center 
The responsibilities of the Johns Hopkins TIC Data Coordinating Center (DCC) in the MAP study include: 
trial design development, monitoring of trial performance, data management planning and execution, 
review and verification of Clinical Coordinating Center (CCC) data for analysis/presentation, statistical 
design and analysis, and reporting of results for various aspects of trial management (e.g., DSMB 
reporting, safety, site performance, study performance), and data sharing (e.g., publications, resource 
sharing). The DCC will collaborate closely with CCC throughout the duration of the trial and will rely on 
study leadership and CCC to provide the appropriate scientific and clinical guidance to ensure the 
successful completion of the responsibilities described above. 
Trial design development 
The statistical core of the DCC will participate in the  following processes: a) Developing study hypotheses 
in collaboration with study PI and study team members; b) Randomization and stratification; c) Blinding 
strategies; d) Defining intervention and control groups; e) Establishing study population and estimating 
sample size; f) Selecting and operationalizing study endpoints; g) Developing Data Safety Monitoring 
Board (DSMB) analysis plan, and h) Developing of Statistical Analysis Plan (SAP) in collaboration with study 
leadership. 
Data management planning and execution 
DCC will ensure that the CRFs include all variables needed to address the study hypotheses, and safety 
and efficacy endpoints; and that no redundant or unnecessary variables are included. DCC will develop 
electronic data capture screens using Prelude Dynamics, LLC VISIONTM EDC system. The design and 
development of the electronic database system will reflect the FDA Guidance for Industry for 
Computerized Systems Used in Clinical Trials (April 1999) as well as the Electronic Records/Electronic 
Signatures rule (21 CFR part 11). 
When data is entered in VISIONTM EDC, a secure and time-stamped electronic record is generated with full 
audit trail. It will allow real-time monitoring of data through reconstruction of the course of events relating 
to the creation, modification, and deletion of an electronic record. Source documents will be retained to 
enable a reconstruction and evaluation of the trial. The system will ensure that all applicable regulatory 
requirements for record keeping and record retention in clinical trials are met.  Additional features of the 

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VISIONTM EDC system include randomization, multi-site access, querying, site management, inventory 
management, invoicing, lab processing, user management and document management. Data from the 
EDC system will be exported in an XML/SAS format at pre-determined intervals. DCC will provide data ETL 
(Extract, Transform, Load) support and make data available in most of commonly used data formats. 
Audit trail 
An audit trail is a record of a sequence of events from which a history may be constructed. All changes 
made to data in the EDC are tracked and recorded in the database. This audit trail will capture the 
date/time, the contents of the changes made, and the login ID used to make the change. Query resolution 
correspondence will be maintained in EDC as well and eCRF edits will be tracked by the system. The audit 
trails will be created incrementally in chronological order with prevention of overwrite and are in 
compliance with the 21 CFR 11.10(e).  Audit trail information will be reviewed by pre-authorized personnel 
if the need arises to verify the quality and integrity of the data. 
Individuals who maintain the EDC system as well as the audit trail will carry the responsibilities to protect 
authenticity, integrity, and confidentiality of electronic records. Audit trails will be available for FDA 
inspectors at the study site or any other location where associated electronic study records are 
maintained. 
Data validation and checks 
The electronic CRFs will be designed to contain the prompts, lookup values, data type and range 
validation, cross-field logic check, and warning/error flags. This process ensures high quality of data is 
collected. On-line help is also available to encourage consistent use of clinical terminology across the study 
sites. 
Security and back-up 
The EDC system will be hosted on high availability servers in secure data center. The server will be strictly 
monitored and maintained by designated administrators at Prelude Dynamics. Users at the participating 
sites will be made aware of system security measures and the importance of limiting access to authorized 
personnel. Access to the data at a clinical site will be restricted and monitored by the system through 
required login, security verification procedures, and audit trail. VISIONTM EDC implements role-based 
access control. It grants user access only to the forms or data fields that they need to see and prevents 
them from accessing data that doesn’t pertain to them.  
Each user will be assigned an individual account with a unique username, password and a role (such as 
investigator, project manager, site coordinator). Any user will be locked out after a pre-determined 
number of consecutive attempts, with any unauthorized access attempt recorded in a log file. Users will 
be required to exit the system upon leaving a workstation. The computer will automatically log off the 
current session when an idle period reaches a pre-determined length. For short periods of inactivity, the 
automatic screensaver will be password protected to prevent unauthorized access to the system. 
Records will be backed up at pre-determined intervals to prevent a catastrophic loss compromising the 
quality and integrity of the data. Data will be backed up onto digital media, which will be stored at an 
offsite location. Backup and recovery logs will be maintained to facilitate an assessment of the nature and 
scope of data loss in the event of a system failure. 
Written procedures describing contingency plans for continuing the study by alternate means in the event 
of hardware or facilities failures with alternate hardware or at an alternate site will be provided to each 
site. It should be noted that the data management procedures will reflect the advanced use of computer 
and software technology; include database technology, and electronic file management principles; and 

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therefore, be of the highest possible standards achievable for data security and information integrity. 
Specifically, the data center is SAS-70 Type II compliant, HIPAA-audited and certified for maintenance of 
banking, credit card, and PHI). 
Organization of Study Data: All study data related documents will be organized as follows: 
• 
Clinical Data: All data collected in the EDC system 
• 
External files: Any data uploaded to the EDC system including PDF versions of consent forms, 
participant source docs, video files, and scans 
• 
Site Management Data: All study site related data and documents collected in the EDC system 
• 
Structural metadata: Information about forms, tables, and visit schedule 
• 
Coding dictionary: Data dictionary indicating the variable names and types, labels and value labels 
for categorical variables 
• 
Lab ranges: Reference ranges for lab values with version control if different versions are used 
• 
Audit trail: Study audit trail maintained in a tamper-proof format 
• 
Listing of edit checks and derived variables: Program files used for edit checks and for creating derived 
variables 
• 
Discrepancy management logs: Listing of records with failed edit checks and information on how they 
were resolved 
• 
Queries: Electronic copies of all queries and query correspondence 
• 
Program code: Syntax code for data edit checks, data derivation and statistical analyses (interim and 
final) performed on the trial data with version control, if applicable 
• 
Data management plan: Electronic copy of SOPs for data management with version control, if 
applicable 
• 
Database lock: Procedures for database lock; final locked, de-identified databases and final analytic 
database(s) used for manuscript generation  
Review and verification of data 
Data quality assurance: Data entry error checks will be programmed and processed at predetermined 
intervals during the course of the study.  The resulting queries will be sent to the site coordinators for 
resolution. Resolutions will be documented in the EDC system.  A list of all queries that cannot be resolved 
will be maintained. 
Weekly/Monthly Reports: DCC will prepare weekly/monthly screening, enrollment, and study monitoring 
reports for each site at pre-determined intervals during the course of the study.  These reports are 
intended to provide input to each site on their performance and areas of improvement. 
Statistical design and analysis 
The statistical core of DCC in collaboration of study leadership and CCC, will develop a study monitoring 
plan and DSMB analysis plan to measure safety, site performance, and study performance and monitoring. 
Reports will be generated at pre-determined intervals by DCC and shared with sites, study leadership and 
DSMB members as appropriate. 
A Statistical Analysis Plan (SAP) will be developed by the statistical core of DCC in collaboration with study 
leadership with detailed information on statistical methods being used for primary, secondary and tertiary 
outcomes, if applicable. 
Reporting of results 

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DSMB analysis plan: Interim safety analyses will be prepared for the external DSMB on a pre-determined 
schedule (such as semi-annually or after enrollment of a fixed number of participants) to evaluate efficacy 
and safety.  Prior to DSMB report generation, the CCC will work with the enrolling sites to finalize the case 
forms and complete the resolution of all pending data queries. DCC will ensure that all the variables 
needed for the DSMB are reviewed and prepare an analytic database.  DCC will then conduct all requested 
analyses, and compile suitable reports, tables and graphs on blinded and unblinded treatment assignment 
data, if applicable. 
SAP: DCC will run the entire database through the edit check programs and deem the database clean and 
locked.  DCC will then create analytic programs with syntax for derived variables and statistical procedures 
along with comments to indicate the purpose of each analysis.  DCC will also generate tables and graphs 
required for the manuscript. 
Data sharing 
Final data archiving: At the conclusion of the study when the database has been locked, all entered 
participant data and uploaded documents in the EDC system will be archived and provided to the site on 
flash drives. Regulations require that study documents (including the archive CDs and any study 
documents not uploaded to the EDC) must be retained in the files of the responsible investigator for 
potential review by regulatory agencies.  
ClinicalTrials.gov: DCC will share the final de-identified analytic database, study protocol, SAP, manual of 
operations, and published manuscript with NIA through a secure NIH dropbox/FTP site for public access.  
The final study results published in the peer-reviewed journal manuscript will be entered into the Protocol 
Registration and Results (PRS) system on the ClinicalTrials.gov website.  After completion of review, 
ClinicalTrials.gov will release study data to the public.   
10.1.9.2 Study Records Retention  
Health Insurance Portability and Accountability Act Under the HIPAA Privacy Rule, participants have the 
right to ask for an accounting of certain disclosures of their identifiable health information for a period 
dating 6 years from the date of the last covered disclosure.  To ensure that sites can meet this accounting 
requirement, investigators must retain study records, along with records of all disclosures of study 
information, for at least 7 years after either of the following (whichever is later): 
• 
The last participant has completed his or her participation in the study; or, 
• 
The date of the last disclosure of identifiable health information from study records if disclosures 
continue after all participants have completed the study.  [45 CFR 164.528] 
This requirement to retain study records and to account for disclosures also applies to research that 
involves the secondary use of medical records or other identifiable health information. 
Federally funded research and FDA-regulated research 
DHHS regulations require that, “records relating to research which is conducted shall be retained for at 
least 3 years after completion of the research.” [45 CFR 46.115(b)] 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  

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It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
within the required number of working days of identification of the protocol deviation.  All deviations 
must be addressed in study source documents, reported to the NIA Program Official and Johns Hopkins 
TIC Data Coordinating Center.  Protocol deviations must be sent to the reviewing sIRB per their policies. 
The site investigator is responsible for knowing and adhering to the reviewing sIRB requirements. Further 
details about the handling of protocol deviations will be included in the MOP.  
Emergency deviations require reporting to the sIRB promptly after they occur   
Emergency deviations are those occurring in an emergency situation, such as when a departure from the 
protocol is required immediately to protect the life or physical well-being of a participant.  In such cases 
there is no time to prospectively seek the approval of the IRB.  The sponsor and the sIRB must be notified 
as soon as possible, but not later than 5 days after the emergency situation occurred (21 CFR 
812.150(a)(4)).  Deviations of this nature are always considered to be unanticipated problems involving 
risks to participants or others (see JHM IRB Policy No. 103.6(b)). 
Major, non-emergent deviations require approval by the sIRB before they occur 
Major, non-emergent deviations are planned deviations that are non-emergent and represent a major 
change in the approved protocol. These deviations are changes the IRB must approve before the proposed 
change is implemented.  Examples include exceptions to eligibility criteria, exceptions to the form and 
manner of obtaining informed consent, and exceptions to the schedule of administration of an 
investigational product.  If a planned major, non-emergent deviation occurs without prior IRB approval, 
the event is non-compliance, which must be reported promptly to the sIRB. A PI’s failure to report 
promptly any major, non-emergent deviation for which the PI did not obtain prior approval is itself an 
incident of non-compliance.  Incidents of non-compliance will be managed in accordance with the JHM 
IRB Organization Policy on Investigator Non-Compliance Policy No. 103.7. 
Minor or administrative protocol deviations require reporting to the sIRB at continuing review 
Minor or administrative deviations are those which do not “affect the scientific soundness of the research 
plan or the rights, safety, or welfare of human subjects.”  If a protocol deviation occurs which meets this 
definition, the deviation should be reported to the JHM IRB at the time the continuing review application 
is submitted in eIRB using the JHM Protocol Deviation Summary Sheet.  Examples of minor or 
administrative deviations include follow-up visits occurring outside the protocol required time frame 
because of the participant’s schedule, or blood samples being obtained at times close to but not precisely 
at the time points specified in the protocol. 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 

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journals. Data from this study may be requested from other researchers 7 years after the completion of 
the primary endpoint by contacting the PI, José Luchsinger, MD.    
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all NIH-
funded research that generates large-scale human or non-human genomic data, as well as the use of these 
data for subsequent research. Large-scale data include genome-wide association studies (GWAS) and SNP 
arrays, genome sequence, transcriptomic, epigenomic, and gene expression data. 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the NIA has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported dualities of 
interest. 
10.2 ABBREVIATIONS 
AD 
Alzheimer’s disease 
ADAS-cog 
Alzheimer’s Disease Assessment Scale-cognitive subscale 
ADCS-PACC 
Alzheimer’s Disease Cooperative Study, Preclinical Alzheimer Cognitive Composite 
ADDF 
Alzheimer’s disease Drug Discovery Foundation 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AGE 
advanced glycation end products 
AE 
adverse event 
aMCI 
amnestic mild cognitive impairment 
ANCOVA 
analysis of covariance 
APA 
Active Place Avoidance 
BMI  
body mass index 
BMP 
basic metabolic panel 
CALM 
Center for Advanced Laboratory Medicine 
CAPI 
computer-assisted personal interviews 
CBC 
complete blood count 
CCMC 
clinical coordinating and monitoring center 
CDR 
clinical dementia rating 
CFR 
Code of Federal Regulations 
CGIC-MCI 
clinical global impression of change for mild cognitive impairment   
CHF 
congestive heart failure 
CMSU 
Clinical Materials Services Unit (at the University of Rochester) 
CoC 
certificate of confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRC 
clinical research coordinator 
CRF 
case report form 

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CTSA 
Clinical Translational Science Award 
CUMC 
Columbia University Medical Center 
DCC 
data coordinating center 
DPP 
Diabetes Prevention Program 
DPPOS 
Diabetes Prevention Program Outcomes Study 
DSMB 
data safety monitoring board 
EC 
ethics committee 
eCRF 
electronic case report forms 
EDC 
electronic data capture 
 
 
ETL 
Extract, Transform, Load 
FC-SRT 
Free and Cued Selective Reminding Test 
FDA 
Food and Drug Administration 
FDG 
F-labeled 2-deoxy-2-fluoro-D-glucose 
GCP 
good clinical practice 
GFR 
glomerular filtration rates 
GLP 
good laboratory practices 
GLP1 
Glucagon like peptide-1 
GMP 
good manufacturing practices 
GPA 
glucagon-like peptide agonists 
GWAS 
genome-wide association studies 
HbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act  
HOMA 
homeostatic model assessment 
IADL 
Instrumental Activities of Daily Living 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
IDE 
insulin degrading enzyme 
IND 
investigational new drug application 
IP 
Investigational product 
IRB 
institutional review board 
ITT 
intention-to-treat 
JHM 
Johns Hopkins Medicine 
JHU 
Johns Hopkins University 
MAC-Q 
Memory Complaint Questionnaire 
MAP 
Metformin in Alzheimer’s dementia Prevention 
MCI 
mild cognitive impairment 
MetMCI 
Phase II trial of metformin in aMCI 
MI 
myocardial infarction 
MOP 
manual of procedures 
MMSE 
Mini-Mental Status Exam 
MRI 
magnetic resonance imaging 
NACC 
National Alzheimer’s Coordinating Centers 
NCATS 
National Center for Advancing Translational Sciences 
NCT 
national clinical trial 

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NHLBI 
National Heart, Lung, and Blood Institute 
NIA 
National Institute on Aging 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PET 
positron emission tomography 
PHI 
protected health information 
PI 
principal investigator 
QA 
quality assurance 
QC 
quality control 
RIC 
recruitment innovation center 
RPR 
rapid plasma reagin 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDV 
source document verification  
SOP 
standard operating procedure 
SNP 
single nucleotide polymorphisms 
SRT 
Selective Reminding Test 
SUSAR 
suspected unexpected serious adverse reaction 
SUVR 
standardized uptake value ratio 
TIC 
trial innovation center 
TICS 
telephone interview for cognitive status 
TSH 
thyroid stimulating hormone 
UBACC 
University of California, San Diego Brief Assessment of Capacity to Consent 
UDS 
uniform data set 
UIP 
University of Iowa Pharmaceuticals 
UP 
unanticipated problem 
US 
United States 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A comprehensive Summary of Changes table for the current 
amendment is provided separately. 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
14 Feb 2020 
See Protocol v1.1 SOC 
Major changes in protocol activities and 
schedule 
1.2 
20 May 2020 
See Protocol v1.2 SOC 
Minor changes and clarifications 
1.3 
29 Sep 2020 
See Protocol v1.3 SOC 
Added PET sub-study 
1.4 
22 Dec 2020 
See Protocol v1.4 SOC 
Minor changes and clarifications 
1.6 
10 Aug 2021 
See Protocol v1.6 SOC 
Updated inclusion/exclusion criteria and 
minor changes  
1.7  
10 May 2022 
See Protocol v1.7 SOC 
Updated inclusion/exclusion criteria, 
verbal consent of study partner, two-
month period from randomization to start 
of study drug to allow for imaging. 
1.8 
30 Jun 2022 
1. Change of study drug kits to non-
site-subject- and visit-specific. 2. 
Addition of option for remote 
consenting by paper. 3. Defining 
physical exam as brief neurological 
exam and anthropometric 
measures. 
1. Facilitate drug supply; 2. Facilitate 
consenting process. 3. Clarify that full 
physical exam is not performed. 
1.9 
24 April 2023 
See Protocol v1.9 SOC 
Two major changes: decrease in sample 
size to 326 from 370 and decrease in 
follow-up duration to 18 months from 24 
months. Other changes are relatively 
minor clarifications. 
2.0 
21 May 2024 
See Protocol v2.0 SOC 
Clarified three exclusion criteria and added 
one additional exclusion criterion. Also 
updated information about plasma AD 
biomarkers and changed them from 
exploratory to secondary outcomes. 
 
Table 8. History of Major Protocol Changes and Rationale 
 
 
 
 
 

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