Effect of Insulin Sensitizer Metformin on AD Biomarkers
Condition: Alzheimer's Disease; Vascular Dementia; Dementia; Memory Impairment
MeSH terms: Alzheimer Disease; Dementia; Dementia, Vascular
Intervention: Metformin; Placebos
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This pilot study used a randomized, double-blinded, placebo-controlled 16 week crossover design to examine the effects of metformin on biochemical, neurophysiological, and cognitive biomarkers of AD.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 20.0
Sex: All
Minimum age: 55 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Alzheimer's Disease; Vascular Dementia; Dementia; Memory Impairment

Summary:

      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of
      memory and other cognitive functions. It is the most common cause of dementia in older
      adults, affecting approximately 18 million people worldwide, including almost 500,000 in the
      Philadelphia tri-state area. After age 65, the incidence of AD rises exponentially, doubling
      every five years. By age 85, almost half of us will have AD. In 2030, as many as 7.7 million
      Americans could have AD, and by 2050 this number could rise to 11-16 million people. The
      annual cost of AD in the United States is about $200 billion. AD-related medical
      complications are among the most common causes of death in the elderly population. Despite
      these alarming statistics, a "cure" for AD may not be essential since delaying the onset of
      AD by just 5 years could have a profound impact on this disorder by reducing the incidence
      and cost of AD by 50% between now and 2050.

      AD is difficult to recognize in its earliest stages, in which the principal complaint is
      typically an increase in episodes of forgetfulness. This stage is now commonly referred to as
      mild cognitive impairment (MCI). Neuroimaging and CSF biomarkers have demonstrated good
      accuracy in predicting which MCI patients later "convert" to AD and which tend to remain
      stable or revert to more normal cognition. The diagnosis of AD itself is made when increased
      loss of memory and other cognitive abilities (eg, language, praxis, and executive function)
      affect daily functioning. As the symptoms of dementia inevitably worsen, patients may become
      incapable of even basic activities such as feeding and dressing themselves. The disease
      course often spans more than a decade, creating a vast social and financial burden on society
      and extracting an immeasurable emotional toll on family members.

      Clinical and preclinical evidence is accumulating that brain insulin resistance may play a
      role in the pathogenesis and/or progression of Alzheimer's disease and that ameliorating
      insulin action in the brain may benefit cognition symptomatically and modify disease
      pathology.
    

Eligibility criteria:

        Inclusion Criteria:

          -  • Ages 55-80.

               -  2 Sex distribution: male and female

               -  Diagnosis of MCI due to AD127 or early dementia due to AD128 with: a) age 55 -
                  80, b) complaint of cognitive decline, c) abnormal performance on the Logical
                  Memory subtest of the Wechsler Memory Scale, d) MMSE > 21, e) CDR 0.5-1, f)
                  positive topographic (MRI, FDG-PET) or molecular (CSF, amyloid imaging) biomarker
                  consistent with AD, and g) no history of diabetes or other exclusions.

               -  Fluent in English or Spanish

               -  Education >5, literate, and/or good working history that precludes consideration
                  of mental retardation

               -  Visual and auditory acuity sufficient for neuropsychological testing and auditory
                  evoked potential EEG

               -  Geriatric Depression Scale < 6

               -  Modified Hachinski Ischemic Score < 4

               -  No major health issues or diseases expected to interfere with the study

               -  Willing to complete all baseline assessments and study procedures

               -  Stable on all permitted medications for 8 weeks

               -  Not pregnant, lactating or of child-bearing potential (women must be >2 years
                  post-menopausal or surgically sterile)

               -  No history of diabetes

               -  Fasting blood glucose <126 and/or HgbA1c < 6.4

               -  Study partner with frequent contact with patient willing to accompany patient to
                  visits and complete partner study forms

               -  No contraindication to metformin

        Exclusion Criteria:

          -  • Any CNS disease other than suspected incipient AD, such as clinical stroke, brain
             tumor, normal pressure hydrocephalus, brain tumor, multiple sclerosis, significant
             head trauma with persistent neurological of cognitive deficits or complaints,
             Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases

               -  Screening/baseline MRI scans with evidence of infarction or other focal lesions
                  in critical memory structures that may be related to cognitive dysfunction

               -  Major active psychiatric illness (e.g., depression, bipolar disorder, obsessive
                  compulsive disorder, schizophrenia) within the previous year

               -  History of alcohol or other substance abuse or dependence within the past two
                  years

               -  Pacemakers, aneurysm clips, artificial heart valves, ear implants, metal
                  fragments or foreign objects in the eyes, skin or body or claustrophobia that
                  would preclude MRI scanning

               -  History of past or current diabetes, pancreatic or liver disease, renal disease

               -  Any significant systemic illness or unstable medical condition that could affect
                  compliance with study

               -  Laboratory abnormalities in B12, TFTs, RPR, Lyme or other common lab parameters
                  that might contribute to cognition or participation in study

               -  Coagulopathy or anti-coagulant therapy (such as coumadin) increasing the risk for
                  LP resulting in PT/PTT and INR within 1.5 standard deviations over the upper
                  normal limit.

               -  Compromised renal function at screening as determined by creatinine clearance
                  <30mL/min based on Cockcroft-Gault calculation

               -  Liver dysfunction at screening as evidenced by alanine transaminase (ALT/SGPT)
                  values > 2X upper limit of normal or aspartate transaminase (AST/SGOT) values >
                  3X or total bilirubin > 2X.

               -  Has received acetylcholinesterase inhibitor and/or memantine and/or any other
                  medicine that affects the central nervous system for less than 4 months or has
                  less than 2 months stable therapy on these treatments by baseline visit.

               -  Current use of specified medications with psychoactive properties that
                  deleteriously affect cognition (e.g., certain antidepressants, anticholinergics,
                  anti-histamines, antipsychotics, sedative hypnotics, anxiolytics)

               -  Use of investigational agents one month prior to entry and for the duration of
                  the trial

               -  Exceptions to these guidelines may be considered on a case-by-case basis at the
                  discretion of the protocol director.