As the US population ages, the prevalence of dementia is increasing, and Alzheimer's Disease (AD) is the most prevalent one. Solving the Alzheimer's Disease (AD) epidemic is likely to require preventive therapy beginning many years before symptoms are expected to be evident in at-risk individuals. AD is caused by the dysfunction, loss of synapses, and eventual neuronal death, which may occur up to 25 years before clinical symptoms appear. This study, based off of pre-clinical data, seeks to assess whether it is feasible to use memantine hydrochloride for the prevention of Alzheimer's Disease.

The use of memantine for prevention of Alzheimer's Disease (AD) is designed to assess the feasibility of the use of memantine hydrochloride for prevention of AD and provide design elements for a Phase 3 efficacy study.

Up to 128 subjects will be enrolled/screened to achieve a sample size of 32 randomized participants with a 1:1 randomization allocation. The study population will include individuals, 50-65 years of age, who are APOE4 positive with a family history of Alzheimer's Disease who meet all other eligibility criteria.

The schedule of assessments includes screening/baseline, treatment period (including titration up/down) and follow up/end of study over 101 weeks for each subject. Study efficacy assessments are the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL), Cognitive Function Index, Alzheimer's Disease Cooperative Study - Activities of Daily Living Prevention Instrument Activities of Daily Living - Prevention Instrument and the Clinical Dementia Rating Scale (CDR) Scale. Safety assessments include the Center for Epidemiologic Studies Depression Scale (CES-D) Vital Signs, Physical/Neurological Exam, Electrocardiogram, Blood Chemistries, Urinalysis, Medical History, Assessment of Adverse Events and Concomitant Medications, MRI and PET imaging.

Inclusion Criteria:

1. Be between the age of 50 and 65 years at time of informed consent.
2. Have a positive family history for dementia (minimum of 1 first degree relative).
3. Previously known or documented heterozygote or homozygote ApoE ε4 allele.
4. Be able to read and write and must have adequate hearing and visual acuity to complete the psychometric tests.
5. Be otherwise healthy for their age group or medically stable with or without medication on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening or at baseline.
6. Have Montreal Cognitive Assessment (MOCA) score of 27 or above.
7. Have a creatinine clearance (CrCl), estimated using the Cockcroft-Gault formula, greater or equal to 30 mL/minute.

Exclusion Criteria:

1. A current clinical condition or requires a medication that raises the pH of their urine.
2. Severe renal or hepatic impairment.
3. Any other abnormality that could cause a possible cognitive deficit (including, but not limited to, vascular encephalopathy or large strokes).
4. Contraindications for MRI (e.g., prostheses, implants, claustrophobia, pacemaker) or PET imaging.
5. Neurodegenerative disorder known to cause neurocognitive decline
6. Relevant history of or current neurological disease other than preclinical AD, which may make interpretation of possible new neurological signs or symptoms difficult.
7. Clinically significant and active pulmonary, gastrointestinal, renal, hepatic, endocrine, or cardiovascular system disease
8. Ongoing cancer treatment
9. Clinically significant and active psychiatric disorder
10. Use of an investigational medical device within 3 months before the planned start of study.
11. Current participation in an interventional study with an investigational drug component.
12. Major surgery (e.g., requiring general anesthesia) within 8 weeks before screening, or will not have fully recovered from surgery, or has major surgery planned during the time the subject is expected to participate in the study.
13. Requires treatment with an AChE inhibitor or any of the following: acetazolamide, methazolamide, amantadine, ketamine, dextromethorphan.