Acute Effects Of Donepezil On Brain Perfusion And Memory In Subjects With Cognitive Impairment And Mild Alzheimer's Disease

Inclusion Criteria:

• Subjects and caregivers must provide written Informed Consent and be willing to complywith scheduled visits, treatment plan, laboratory tests, and other trial procedures.

• AD: Diagnostic evidence of probable AD consistent with Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) and National Institute ofNeurological and Communicative Disorders and Stroke and the Alzheimer's Disease andRelated Disorders Association (NINCDS-ADRDA) criteria met by the site Physician at thetime of the Screening visit. This evidence must be fully documented in theparticipant's file prior to the Baseline Visit.

• For amnestic Mild Cognitive Impairment (MCI): A Clinical Dementia Rating (CDR) of 0.5 (with memory box score of at least 0.5) and a memory complaint that is objectivelyverified using a test of episodic memory: Delayed recall from one paragraph of theWechsler Logical Memory scale (cutoff scores by education - maximum score of 25).

• Less than or equal to 8 for 16 or more years of education; Less than or equal to 4 for 8-15 years of education; Less than or equal to 2 for 0-7 years of education.

• Mini Mental State Exam (MMSE) score of 21-30

• Male and female subjects of non child-bearing potential (or using appropriate birthcontrol measures) who are at least 50 years of age.

• In generally good health, in the opinion of the Principal Investigator (PI), based onmedical history, Body Mass Index (BMI), physical examination, vital signs, 12-leadECG, and laboratory values, including hematology and chemistry values.

• No known genetic AD causes for early onset memory impairment (e.g., presenilinmutation), participants from a family with known autosomal dominant AD associated withmutations in APP, PS1, or PS2 genes or strongly suspected, but not yet identifiedmutations in APP, PS1 or PS2 genes or Down's syndrome are not eligible to enroll.Individuals from families with late onset AD with 2 or more affected family membersmay participate. Type II diabetic subjects may be included provided that their disease and serum glucosevalues are controlled and being actively managed, as assessed by the PI using a fastingblood sugar and/or HgbA1C (per the PI's medical judgment in consultation with the Sponsor).

• Rosen-Modified Hachinski Ischemia Score less than or equal to 4.

Exclusion Criteria:

• Diagnosis or history of other possible cause for or significant contributor todementia, including but not limited to other neurodegenerative disorders (eg,frontotemporal dementia, Lewy body disease, vascular dementia), vitamin B12 deficiency (reflex Methylmalonic Acid (MMA) and folate if B12 is low), untreated thyroid disease,syphilis, alcoholism, severe or recurrent head injury that is clinically relevant tothe disease under study, or onset of dementia following heart surgery or cardiacarrest.

• Diagnosis or history of cerebrovascular disease (eg, stroke, transient ischemicattack), severe carotid stenosis, cerebral hemorrhage, intracranial tumor,subarachnoid hemorrhage, or subdural hematoma that could contribute to the subject'scurrent cognitive or functional status, impair ability to fully participate in thetrial or that may impact status during the one week study.

• Specific exclusionary brain MRI findings identified prior to study or at baseline asdetermined by the investigator that could either contribute to the subject's currentcognitive or functional decline impair ability to fully participate in the trial orthat may impact status during the trial:

• History of cancer within the last year (except for cutaneous basal cell, squamous cellcancer resolved by excision, colon polyp resolved by excision, or non-progressiveprostate cancer per investigator's judgment).

• History of clinically significant cardiovascular or renal events.

• Subjects with uncontrolled hypertension even with therapeutic intervention

• History of clinically significant (as determined by the PI in consultation with theSponsor) syncope, seizure, head trauma, or clinically significant unexplained loss ofconsciousness within the last 5 years.

• A diagnosis of major depressive disorder or other psychiatric illness as the primarydiagnosis per the DSM-IV text revision (TR) criteria per the investigator's judgment.

• History of schizophrenia, bipolar disorder, or other severe mental illness.

• Known history of alcohol or drug abuse (as defined by the DSM-IV-TR) within 5 yearsprior to dosing or a positive result regarding use of illicit drugs on the drugscreening test.

• History of clinically significant symptoms of pulmonary disease that requirestreatment (eg. asthma, COPD, or other chronic respiratory conditions).

• Known positive Human immunodeficiency virus (HIV) status.

• Unwilling or unable to comply with the Life Style guidelines described in thisprotocol. Exclusions Related to Medications or Procedures

• Treatment with an investigational drug within 30 days or 5 half-lives (whichever islonger) of Study Day 1.

• Use of tobacco- or nicotine-containing products within three months of study Day 1. Use of medication(s) for cognitive enhancement ≤ 90 days before the first dose of studymedication.

• Prescription: including but not limited to donepezil, galantamine, rivastigmine,tacrine, memantine, Axona™;

• Reason for stoppage of donepezil may not be related to tolerability issues or to gainentry in this study.

• Non-prescription treatments for cognitive enhancement.

• Subjects with either non-removable ferromagnetic implants (such as cardiacpacemaker), aneurysm clips or other foreign bodies that would contraindicate abrain MRI scan.

• A clinically significant (as determined by the PI) abnormality in the 12-leadECG, including complete heart block, bradycardia (heart rate <40 beats/minute),sinus pauses >2 seconds, second or third degree heart block, QTc >450 or otherabnormalities judged clinically significant by the PI.