A Pilot Clinical Trial of Exendin-4 in Alzheimer's Disease

* INCLUSION CRITERIA: * Age \> 60 * Clinical Dementia Rating (global CDR) of 0.5 or 1. Memory box score must be at least 0.5. * Mini Mental Status Exam (MMSE) \> 20 * Clinical diagnosis of (amnestic or mixed) MCI or early AD and Memory deficit on neuropsychological or clinical testing. * Hamilton Depression Scale score of less than or equal to 12 on the 17-item scale * CSF A beta 42 \< 192 (+- 10%) pg/ml (given an intra-subject laboratory variability \~ 10%) * Medications stable for at least 4 weeks prior to screening. In particular: * Participants may take stable doses of antidepressants, chronic anxiolytics or sedative hypnotics, if started at least 4 weeks or longer prior to screening * Cholinesterase inhibitors and/or memantine are allowable, if started at least 4 weeks prior to screening * Participants will not be asked to discontinue medications without permission from their primary care provider (PCP) or specialist. * Fluency in English * At the time of enrollment, participants must have the ability to provide informed consent and make health care decisions. * An informant or caregiver who has frequent contact with the participant (e.g. an average of 10 hours per week or more) must be appointed to serve as Durable Power of Attorney (DPA) for research and medical care at NIA, accompany the participant to clinic visits and provide historical information regarding the participant s cognitive status, and assist participants with/administer injections of the investigational medication. * Good general health with no additional disease states that could interfere with the study. EXCLUSION CRITERIA: * Other significant neurological disease of the Central Nervous System (such as Parkinson s disease, atypical Parkinsons disease, Multi-infarct Dementia, Frontotemporal Dementia, Huntington s disease, Normal Pressure Hydrocephalus, brain tumor, Progressive Supranuclear Palsy, Epilepsy, Subdural Hematoma or Multiple Sclerosis) * A history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities * Positive RPR or HIV * Abnormal PT/PTT and INR (1.5 standard deviation over the upper normal limit) increasing the risk for LP related bleeding/hematoma; platelet count \<100,000/microliters. * Anti-coagulant therapy (such as coumadin). Aspirin up to 325 is allowed. * Investigators unable to obtain CSF, failure of Lumbar Puncture after a limited number of unsuccessful attempts). * History of psychiatric disease with significant impairment in thought processes (e.g. schizophrenia, bipolar disease, psychosis). Participants who develop psychiatric conditions necessitating treatment after their enrollment will not be dropped from the study. The high incidence of late-onset depression and anxiety among individuals with MCI and AD requires that participants with depression, and/or anxiety should not be excluded from the cohort to maintain the ecological validity of the results. * Current abuse of alcoholic beverages (\> 7 in women and \>14 in men) or substance abuse. * Known diagnosis of diabetes at the time of enrollment or new diagnosis of diabetes based on the findings of elevated fasting blood glucose (= or \>126 mg/dl) and/or the oral glucose tolerance test at screening (\>200 mg/dl at two hours). * Severe renal impairment (creatinine clearance \<30 ml/min) or end-stage renal disease. Individuals with moderate renal impairment (creatinine clearance 30 to 50 ml/min) may be enrolled in the study, but their BUN and Creatinine will be monitored during each visit after drug initiation and extra safety visits will be conducted at 3, 9, and 15 months. * Current or previous treatment with Exendin-4 (Exenatide, trade name Byetta.) * History of pancreatitis, active upper GI, hepatic or gallbladder disease * Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 * History of repeated hypoglycemia * Body mass index (BMI) \< 18 on enrollment (given the expected weight loss caused by Exendin-4 and dementia). In the BLSA, participants with age \> 65 had a mean BMI of 25.8 with SD of 3.9 Exendin-4 has been shown to cause an average 5.3 kg weight loss, with 95% CI: 6 to 4.5 kg (126). * Allergy to Exendin-4 or to substances in the injection pen (metacresol, mannitol, glacial acetic acid, sodium acetate trihydrate, water for injection). * Participation in other studies of investigational treatments for Alzheimer s disease in the last year.