Metformin in Amnestic Mild Cognitive Impairment
Condition: Mild Cognitive Impairment
MeSH terms: Cognitive Dysfunction
Study type: Interventional
Phase: Phase 2

Summary: 
      Hyperinsulinemia and type 2 diabetes (T2D) are important potential risk factors for cognitive
      decline and Alzheimer's disease (AD). Two thirds of the US adult population are at risk for
      hyperinsulinemia and T2D, and half of the population 85 years and older have AD. Peripheral
      hyperinsulinemia can impair the clearance of amyloid beta in the brain, the main culprit in
      AD. Thus, the investigators hypothesize that lowering peripheral insulin in overweight
      persons with amnestic mild cognitive impairment (AMCI), a transition state between normal
      cognition and AD, can decrease the risk of cognitive decline and progression to AD. The
      investigators propose to conduct a phase II double blinded placebo controlled randomized
      clinical trial of metformin, a safe and effective medication that prevents hyperinsulinemia
      and diabetes, to test this hypothesis among 80 overweight persons aged 55 to 90 years with
      AMCI. The main outcome of the study will be changes in performance in a memory test (total
      recall of the Selective Reminding Test) and the Score a test of general cognitive function
      used in clinical trials (the Alzheimer's Disease Assessment Scale-cognitive subscale
      (ADAS-Cog)). Another aim is to compare brain function in an area affected by Alzheimer's
      disease between the metformin and placebo group mean changes from beginning to end among 40
      participants using a PET scan.
    

Detailed description: 
      The prevalence of Alzheimer's disease (AD) is expected to quadruple by the year 2047. There
      are no known curative or preventive measures for AD. Current treatment options for AD only
      address symptoms, and no treatments are available that focus on delaying the actual disease
      process. One of the currently accepted hypothesis of the pathogenesis of AD is that the main
      culprit is the accumulation of Aβ in the brain, and this process has become a target for
      treatments and preventive measures. Amnestic mild cognitive impairment (MCI) has been used to
      describe a transitional state between normal cognitive function and AD, and has thus been
      targeted for interventions. Persons with MCI progress to AD at the rate of nearly 10% to 15%
      per year. The criteria most commonly used for the definition of AD dementia from MCI. The
      investigators propose to use these criteria with slight modification to recruit persons for a
      pilot trail of AD prevention in persons with amnestic MCI.

      Peripheral hyperinsulinemia (high insulin levels) potentially impair Aβ clearance, and in
      this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by
      improving Aβ clearance in the brain. The insulin resistance syndrome and hyperinsulinemia are
      common in individuals with and without diabetes, and are related to increased risk of
      cardiovascular and cerebrovascular outcomes. Hyperinsulinemia predicts the development of
      diabetes; therefore, diabetes can be considered a consequence and a marker of past
      hyperinsulinemia. According to NHANES III data, more than 40% of the population over the age
      of 60 years has problems of glucose intolerance or diabetes, all related to insulin
      resistance and hyperinsulinemia. The investigators have found that the risk of AD in
      individuals without diabetes increases with increasing levels of fasting insulin, and that
      high insulin levels are related to a faster decline in memory scores. The high prevalence of
      hyperinsulinemia and diabetes (49% of the elderly in Northern Manhattan) and its biological
      plausibility as a risk factor for cognitive decline and AD has attracted increasing
      attention. In this application we are targeting hyperinsulinemia, the most important risk
      factor for AD identified in the elderly population of Northern Manhattan. The risk of AD
      attributable to hyperinsulinemia or diabetes in Northern Manhattan was 39%, and is higher in
      Hispanics and African-Americans, who have a higher prevalence of diabetes and insulin
      resistance, and will comprise the majority of our sample.
    

Intervention name(s): Metformin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Metformin 1000 mg twice a day titrated from 500 mg once a day; Placebo identical to metformin 2 tablets twice a day titrated from one table once a day
Other intervention name(s): Glucophage
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Metformin; Mild Cognitive Impairment (MCI); Alzheimer's Disease (AD); Overweight; Insulin