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.

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.

2 years, 5 months