Senicapoc in Alzheimer's Disease

Inclusion Criteria:

• Age 55-85

• Fluent in either English or Spanish

• Willing to be randomized to active drug (10 mg Senicapoc) vs. placebo (3:1 ratio)

• Clinical Dementia Rating (CDR) global score of 1 or 0.5

• Education adjusted scores between 12-28 on the Montreal Cognitive Assessment (MoCA)at the Screening visit.

• A consensus clinical diagnosis of either amnestic Mild Cognitive Impairment (MCI) ormild AD dementia. Diagnoses are made by a comprehensive case conference review forall participants in the ADRC longitudinal cohort and all CADC referrals, resultingin a consensus diagnosis made according to current research criteria. For patientsreferred from other clinics, the case will be reviewed by a study physician andneuropsychologist and only patients who satisfy criteria for probable AD (McKhann etal 1984) or amnestic MCI (Petersen et al 2004) will be eligible for enrollment.

• Vision (with or without correction) of at least 20/50 for distant vision

• All participants will need a study partner informant who has at least 6 hours ofcontact per week with the participant. The study partners are used to help answerquestions on the subject's behalf, since many of them will be impaired and may needassistance with providing accurate information. The study partners are not asked toprovide any opinions or judgements about the subjects.

• For Females of childbearing potential: Must agree to practice a highly effectivemethod of contraception throughout the study until completion of the Week 78 followup visit. Highly effective methods of contraception are those that alone or incombination result in a failure rate of less than 1% per year when used correctlyand consistently.

Exclusion Criteria:

• Unstable medical illnesses including hepatic insufficiency (elevated ALT, AST, orGGT; or low albumin attributable to liver disease), renal insufficiency (CK-EPIstage 4 or higher, or estimated GFR <30)

• Unstable ischemic cardiovascular disease, respiratory failure, moderate or severecongestive heart failure - New York Heart Association class III or IV, cancer,unstable hematologic disease or a life expectancy of <3 years

• Use of experimental AD treatments

• Unable to undergo MRI scanning (e.g. pacemaker, metallic implants, severeclaustrophobia)

• History of chronic psychiatric illness (e.g. schizophrenia), any episode of majordepression within last 2 years, or current Geriatric Depression Scale (GDS) > 6, anyrecent suicide attempts or suicidal ideation. Subjects with a diagnosis of bipolardisorder may be included if they have been clinically stable for a minimum of 3years prior to the Screening visit. Clinical stability to be determined by thePrincipal Investigator.

• History of a serious infectious disease affecting the brain (includingneurosyphilis, meningitis, or encephalitis), head trauma resulting in any persistentcognitive deficit

• History of alcohol or drug abuse/dependence within the past 5 years

• Known allergy to chemically related compounds (e.g. clotrimazole)

• Lack of good venous access, such that multiple blood draws would be precluded

• Regular use of any of these CNS active medications: benzodiazepines, antipsychotics,narcotics, or anti-epileptic drugs. Exceptions may be allowed by the PrincipalInvestigator for regular use of low doses of CNS active medications. Subjects usingany of these treatments will be instructed to hold their dose on the evening priorand the day of the efficacy visits (Baseline, Week 26 and Week 52). Stable doses (> 6 weeks) of cholinesterase inhibitors or memantine will be allowed, as will stabledoses of anti-depressants.

• Female subjects who are pregnant or breastfeeding or who plan to become pregnantduring participation in this trial

• Inability to swallow oral tablets

Exclusions for Cerebrospinal Fluid (CSF) Sub-study:

• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter

• History of bleeding diathesis or coagulopathy,

• On anticoagulant therapy (within 14 days of lumbar puncture (LP), including but notlimited to warfarin, heparin, dabigatran, rivaroxaban, and apixaban,

• Requires daily antiplatelet therapy, including but not limited to aspirin (unless < 81mg/day), clopidogrel, dipyridamole, and ticlopiidinegrel. However, theinvestigators will not exclude those who can safely hold antiplatelet therapy for 7days prior to LP. Safety will be determined by the participant's Primary CareProvider and study PI.

• For those who take antiplatelet therapy intermittently (e.g. aspirin as needed forpain), the investigators will exclude any doses within 48 hours of the LP or morethan two dosses within 7 days of LP.

• platelet count less than the lower limit of normal (platelet counts between 100,000and 150,000 mm3 are permissible as long as the investigator confirms there is noevidence of current bleeding diathesis or coagulopathy)

• The investigators will require INR/PT and aPTT labs to be done within 14 days of LPand will exclude those with INR > 1.30 or abnormally elevated aPTT.

Exclusions for PET Sub-Study:

• Does not have good venous access, such that multiple blood draws would be precluded

• Prior radiation exposure of > 2 rem total within last 12 months.

• Probable AD dementia patients with a global cortical SUVr < 1.08.