STUDY PROCEDURES AT THE LEVEL OF THE PARTICIPANT.

1. 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 (age, language), medical history, contraindications to metformin, and medications. In-person screening includes consent, in-person anthropometric measurements (height, weight, waist and hip circumference), vital signs (blood pressure and heart rate), EKG, laboratory tests (TSH, RPR, vitamin B12, complete blood count \[CBC\], basic metabolic panel \[BMP\], Hepatic panel, Lipid panel, and Hemoglobin A1c \[HbA1c\]), and the in person-neuropsychological battery that is used to determine aMCI.
2. Baseline/screening study visit. History includes age, handedness, education, occupation and employment history, past medical history, and all medications utilized, including a judgment as to whether they affect cognition (positively or negatively). Referral source is also documented. 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 screening. A full medical history will be obtained only at screening. Any report of events, or side effects will prompt a full history and physical exam at any visit. Physical exam will be conducted at screening, with particular emphasis on signs of congestive heart failure, pulmonary, liver, or renal disease for contraindications to metformin, and neurologic examination for the presence of neurologic diseases. Vital signs including blood pressure and heart rate will also be ascertained. 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, 3 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.

   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 1 short story that consists of 25 bits of information will be elicited immediately after it is read aloud to the subject 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. 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 7 rows with 1 of 9 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 subject 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 2 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 0 (worse) to 30 (perfect). Trail-Making Test, Part A: This test of visuoperceptual 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 visuoperceptual ability, attention and set-shifting ability consists of 25 circles distributed over a white sheet of 8 1/2\" X 11\" paper that are either numbered (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. ADAScog12. This test will be used as part of the core battery and assesses memory, reasoning, naming, orientation, ideational praxis, constructional praxis, spoken language, language comprehension, word finding difficulty, and ability to remember test instructions. The addition of a 10 word delay recall adds sensitivity in aMCI and yields maximum score of 80. Functional abilities: ADCS-ADL-PI:The ADCS-ADL-PI was developed in the ADCS Prevention Instruments Trial. The subject rates his/her 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. 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 subject and study partner, using a structured interview that assesses 6 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 6 categories of function are synthesized into 1 global rating of dementia (ranging from 0 to 3), with more refined measure of change available by use of the Sum of Boxes (CDR-SB). Reliability and validity has 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. Cognitive diagnoses. The research physician will complete the National Alzheimer's Coordinating Centers (NACC) Assessment and Uniform Data Set (UDS), which takes 35 minutes and includes detailed medical and family history, and neurological exam, including the Unified Parkinson's Disease Rating Scale for extrapyramidal signs, psychiatric assessment with the short version of the Geriatric Depression Scale and Neuropsychiatric Inventory (NPI) questions, assessment of vascular risk factors plus the Hachinski scale, and a Clinical Dementia Rating (CDR). 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 monthly consensus meetings or calls. This panel will be comprised of co-investigators Luchsinger, Goldberg, Devanand. During the meeting information of all the cognitive, functional and other clinical information of the subjects 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.
3. Randomization. Eligible participants will be randomized in 1:1 ratio to receive either metformin or placebo, using randomly permuted block randomization of size two or four by each site to achieve balance of treatment assignment overall and by site.
4. Titration. After participants consent, are deemed eligible, and complete the baseline assessment, they will complete a 30-day titration period in which the metformin/placebo dose will be increased from 500 mg a day at randomization in increments of 500 mg every 10 days to a maximum of 2,000 mg a day. Participants will have in person visits every 10 days to check on their drug/placebo tolerance.The metformin tablets are taken together as a single dose, usually recommended once at night. Participants will remain on the highest dose tolerated.
5. Baseline Brain MRI. Participants will be invited to have a baseline brain MRI without contrast. We expect that brain 3T MRI will be conducted in 186 participants across all sites. MRI sequences will include 3Plane Gradient Echo Localizer, 3D MPRAGE T1, 3D T2, DTI 30 direction, DTI 30 direction, pCASL Axial, pCASL Axial Calibration. Acquisition of these sequences will take approximately 50 minutes.
6. Baseline Brain 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.
7. Baseline Tau PET: Tau PET acquisition will entail injection of 10 mCi of MK6240 with imaging from 90-110 min after CT or transmission scan.1086. Monthly and ad-lib follow-up calls, text messages, or mails. We will conduct monthly follow-up calls to inquire about adverse events and issues with metformin tolerance. We will use the ADCS Adverse Event Checklist to monitor adverse events.
8. Follow-up visits: We will repeat all clinical (non-brain imaging) assessments at months 6, 12, and 18. The only exception is that we will test TSH and RPR only at baseline. All other laboratory tests will be repeated. Pill counts will be conducted to assess compliance with metformin and placebo. We will administer the adverse events checklist. All remaining study drug or placebo will be retrieved to assess compliance and for disposal.
9. Follow-up Brain MRI. Participants who undergo a baseline MRI will be invited to have a follow-up brain MRI with the same sequences after the completion of the last visit at month 18. The MRI will be completed within one month of the last visit.
10. Follow-up Brain Amyloid PET: Participants who underwent baseline amyloid PET will be invited to repeat the PET at 18 months.
11. Follow-up Tau PET: Participants who underwent baseline Tau PET will be invited to repeat the PET at 18 months.
12. Monthly and ad-lib follow-up calls, text messages, or mails. We will conduct monthly follow-up calls to inquire about adverse events and issues with metformin tolerance.