Metformin in Alzheimer's Dementia Prevention

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. Participants must have:

* Subjective memory concerns reported by participant, study partner, or clinician.
* A mini-mental state exam between ≥ 22 for subjects with more than 8 years of education. For subjects with less than 8 years of education, a MMSE ≥ 20 will be allowed.
* Clinical Dementia Rating = 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.
* General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit.
* 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 of 6.5 % or greater) they will also 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 an informant 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.

Exclusion Criteria:

* Use of metformin or any class of medication approved for treatment of diabetes, even if it is used for an indication other than diabetes (e.g., obesity), within one 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 the medication is recommended for those on metformin; 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.
* 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 other 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

History of adverse reactions to radiocontrast agents.