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 A�� 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. We propose to use these criteria with slight modification to recruit persons for a pilot trail of AD prevention in persons with amnestic MCI.

Hyperinsulinemia, diabetes, and risk of AD. Peripheral hyperinsulinemia (high insulin levels) potentially impair A�� clearance, and in this study we are proposing to use metformin, an insulin lowering agent, to prevent AD by improving A�� 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. We 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 Choice of metformin as treatment agent:. The Diabetes prevention program (DPP) is a trial of metformin vs. lifestyle intervention (diet and exercise) vs. Placebo in the prevention of onset of diabetes in 3,234 individuals without diabetes at baseline. It found that both metformin and lifestyle intervention were successful in preventing diabetes vs. placebo in 3 years of follow-up and in reducing insulin levels. Serious adverse events of metformin including hospitalizations and hypoglycemia were similar to placebo. More recently, another agent that lowers insulin levels, rosiglitazone, was tested in similar fashion for the prevention of diabetes and found effective, and is now being tested in AD given its insulin decreasing properties. However, rosiglitazone’s safety profile is not as good as metformin- it can cause, edema and heart failure(21), and is not widely using in clinical practice in persons without diabetes, as metformin is.

The primary aim of this study is to conduct a 12 month pilot placebo controlled randomized trial of metformin in the prevention of memory decline in 40 persons with amnestic MCI, comparing decline of the modified Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-COG) between metformin and placebo. We will also examine the secondary outcome of plasma amyloid beta (A��).

Randomization: We propose the use of random permuted blocks as the method of randomization to ensure balance in the groups given the small sample size. If participants are included in the study we will do APOE-��4 genotyping and use this information for block randomization.

Metformin Dosing Schedule and side effects: Metformin and matching placebo will be provided by Merck-Lipha of France. The medication and placebo will be managed and dispensed by the Research Pharmacy at Columbia University Medical Center. Persons will first be given metformin 500 mg once a day at baseline. At day-7 the dose will be increased to 500 mg twice a day. At day 14, the dose will be increased to 500 mg three times a day. At day 21, the dose will be recommended to 1000 mg twice a day. At day 28, we will call the patient via telephone to ascertain that they are tolerating the dose of 1000 mg twice a day, the usual maximum dose recommended in clinical practice. If the participants report not tolerating a dose of metformin, they will be asked to remain at the lowest tolerated dose. The most common side effect of metformin is gastrointestinal intolerance. At baseline, 3 month, 6 month, 9 month visit and at the end of the study we will measure renal function, liver function, and complete blood count to monitor side effects. This information will be made available to the data safety monitoring board of the study.

C.4.5. Plasma A��40 and A��42 have been suggested as markers of AD and high A��42 has been shown to predict AD progression in Northern Manhattan . They will be measured in all participants at baseline and at the end of the study from EDTA plasma stored a -80 degrees F using published procedures.

General chemistry, liver function tests, and complete blood count will be done as shown in the timetable to monitor for contraindications and side effects of metformin. In persons with no available information on TSH, B12, and RPR, necessary measures to rule out secondary cognitive impairment, we will obtain them at baseline. HsCRP, insulin, lipids, adiponectin, and HbA1c are inflammatory and metabolic intermediate variables and will be measured to ascertain the effects of metformin and to explore mechanisms for a benefit of metformin on the outcomes. APOE-��4 genotyping will be done in the ICCR.

Statistical analyses. The primary analysis, comparing the total recall of the modified ADAS-COG at the end of the study between the placebo and the metformin groups will be on an intention-to-treat basis. We will use ANACOVA to compare between the modified ADAS-COG score and plasma amyloid adjusting for demographic differences and baseline values. In a well conducted randomized trial, all confounders should be balanced with randomization.

In secondary analyses, we will relate the study arms to other outcomes (MCI-ADL, SRT), changes in metabolic and inflammatory markers.

Given that this is a small pilot trial, that the duration of the intervention may not be sufficient, and that one of the objectives of the study is to determine feasibility of the procedures and intervention, examine effect sizes, we will examine with the Institute for the Study of Aging and with other investigators the merits of a larger trial if there is no indication of a benefit of metformin in our study.

A second arm of the study will compare on an intention-to-treat basis between the metformin and placebo group mean changes from teh beginning to end of the trial in uptake of flurodeoxyglucose (FDG) in the posterior cingulate measured with brain positron emission tomography (PET) in 40 non-diabetic patients out of the 80 study subjects. PET imaging will be performed with a HR+ scanner at Columbia Kreitchman PET Center. All image analysis will be performed with MEDX and FSL (FMRIB) Software Library). There will also be a brain magnetic resonance imaging (MRI). MRI images co-registered to the PET images allow accurate structural localization of metabolic changes and correction of brain atrophy. Participants will be scanned on a 1.5T Philips Intera dedicated research scanner. Four sets of structural images will be obtained from each subject during their MRI scanning session. The total imaging time will be 30 minutes. As part of standard procedures, a neuroradiologist conducts a clinical evaluation to rule out tumors, strokes, and other lesions. Any significant abnormality is discussed with the study investigator, who then takes appropriate action, including discussion of the abnormality with the participant, and with the participant’s permission, with the participant’s physician of choice. If the participant has no physician, we will facilitate one at Columbia University Medical Center. PET and MR images will be spatially normalized to a custom template image in standard Montreal Neurological Institute (MNI) space. The spatial normalization will allow assessing any changes in the metabolic rate of glucose as a result of the intervention through a statistical parametric mapping approach. These spatial parameters will be applied to the co-registered PET images thereby transforming them into standardized space.

Inclusion Criteria:

• Age range: 55 to 90 years;

• Sex distribution: men and women;

• Languages: fluent in English or Spanish.

• Subjects must score below a pre-determined cut-off score on the logical memory II delayed paragraph recall sub-test of the Wechsler Memory Scale Revised (WMS-R)26:

  1. less than or equal to 8 for 16 or more years of education.;

  2. less than or equal to 4 for 8-15 years of education;

  3. less than or equal to 2 for 0-7 years of education.

• Global Clinical dementia rating (CDR) score must be 0.5 at screening. The memory box score must be 0.5 or 1.0, with no more than two box scores other than memory rated as high as 1.0 and no box score rated greater than 1.0.

• Subjects without a known history of diabetes or diabetes that has never been treated with medications. If diabetes is diagnosed during screening or they have a history of diabetes not treated in the last 12 months they will be excluded if their HbA1c is > 6.5.

• BMI ��� 25 kg/m2

• No contraindications to metformin treatment.

• General cognition and functional performance such that a diagnosis of dementia cannot be made at the time of screening based on DSM-IV criteria.

• Vision and hearing must be sufficient for compliance with testing procedures.

Exclusion Criteria:

• Subjects with uncontrolled hypertension (systolic blood pressure ��� 160 mmHg or diastolic blood pressure ��� 95 mmHg;

• Subjects with a history of active cancer or cancer within last five years, with the exception of squamous or basal cell carcinoma of the skin;

• Subjects who for any reason may not complete the study as judged by the study physician;

• Abnormal TSH, B12, and RPR.

• Contraindications to metformin use include a creatinine of > 1.5, liver disease by history or by elevated transaminases, congestive heart failure, and alcohol abuse.

• We will also exclude subjects with a history of intolerance to metformin.