Anti-viral Therapy in Alzheimer's Disease

1. Males and females. Females must be postmenopausal defined as 12 consecutive months without menstruation. Patient Report
2. Diagnosis of probable AD by NIA clinical diagnostic criteria. Physician Evaluation
3. Folstein Mini Mental State (MMSE) score 18 to 28 (inclusive) out of 30. Neuropsychological Evaluation
4. Clinical Dementia Rating (CDR) score of 1 (mild dementia). Physician Evaluation
5. A family member or other individual who is in contact with the patient and consents to serve as informant during the study Patient Report
6. Patient retains capacity to consent for him/herself or retains the capacity to identify a surrogate who will consent on his/her behalf. Patient Report
7. At screening, patients must test positive for serum antibodies to HSV1 or HSV2. Patients that test equivocal (index between 0.90-1.09; \< 0.90 is negative and > 1.09 is positive) will repeat the test within 6 weeks at a repeat visit. If the results are negative at the second test, the patient will not enter the study. If the results are equivocal or positive at the second test (first test was equivocal), we will enroll the patient in the study because "equivocal" indicates the presence of antibodies that do not reach the minimum threshold.
8. Use of cholinesterase inhibitors and memantine, and concomitant psychotropic medications (other than high dose benzodiazepines), will be permitted throughout the trial. Doses of these medications will need to be stable for at least 1 month prior to study entry. Any changes to the medication will be documented in the participant research chart. Medications given for other medical reasons, e.g., anti-diabetic or antihypertensive medications, will not be altered for the purposes of this trial and the patient's primary physician may adjust such medications as medically indicated throughout the trial. Details of concomitant medication use will be documented at all visits and will be available for statistical analysis.
9. For patients diagnosed with Mild Cognitive Impairment and CDR score of 0.5 ( questionable dementia), if these patients have biomarkers of AD neuropathology with either a positive amyloid PET scan, positive fluorodeoxyglucose (FDG) PET scan of the brain, or positive findings for AD in CSF ( low ABeta42 and high tau, p-tau protein levels) they will be eligible for the study. This applies to patients who already had an amyloid PET scan, FDG PET scan of the brain, or lumbar puncture, prior to recruitment into the protocol.

Physical Evaluation

Exclusion Criteria:

1. Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study instructions. Physician Evaluation
2. Patient has dementia predominantly of non-Alzheimer's type, including vascular dementia, frontotemporal dementia, Lewy body dementia, substance-induced dementia. Physician Evaluation
3. Modified Hachinski scale score greater than 4. Physician Evaluation
4. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, bipolar disorder or current major depression by DSM-5 criteria. Prior history of major depression will not be exclusionary (25% of older adults have a lifetime history of major depression). Physician Evaluation
5. Active suicidal intent or plan based on clinical assessment. Physician Evaluation
6. Current or recent (past 6 months) alcohol or substance use disorder (DSM-5 criteria). Physician Evaluation
7. Current diagnosis of other major neurological disorders, including Parkinson's disease, multiple sclerosis, CNS infection, Huntington's disease, and amyotrophic lateral sclerosis. Physician Evaluation
8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion. Physician Evaluation
9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases in the last 12 months will be excluded, but past history of successfully treated cancer will not lead to exclusion. Physician Evaluation
10. Sitting blood pressure > 160/100 mm Hg. Physician Evaluation
11. Renal failure as determined by an estimated Glomerular Filtration Rate (GFR) \< 44 ml/min/1.73m2 (see 4.3.b.). Physician Evaluation/ Laboratory Report
12. Serum vitamin B12 levels below the normal range. Physician Evaluation/ Laboratory Report
13. Patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome will be excluded. Physician Evaluation
14. Use of benzodiazepines in lorazepam equivalent doses equal to or greater than 2 mg daily. Physician Evaluation
15. For patients consenting to lumbar puncture (40% of sample), this procedure will be conducted if there is no lower spinal malformation or other contraindication to lumbar puncture. Physician Evaluation
16. For MRI, metal implants and pacemaker, and claustrophobia such that the patient refuses MRI. In the investigators' experience, these exclusions occur in less than 5% of patients with mild AD. MRI is required for VALAD. Patient Report/ Physician Evaluation
17. Radiation exposure in the prior 12 months that, together with 18F-Florbetapir and 18F--MK-6240 PET, will be above the FDA annual radiation exposure threshold. This will be determined through study staff ( i.e. Principal Investigator, Study Physician) discussion with potential subjects at Screening, documenting inquiry about radiation history. If there is any history of additional radiation exposure in the past year; it will be reviewed with PET Center staff for their approval before proceeding. The combined radiation exposure from the maximum doses used for 18F-Florbetapir and 18F-MK- 6240 is within the FDA limits for annual radiation exposure and the second scan in each patient will be done 18 months after the initial PET scan (for both radioligands). Patient Report/Physician Evaluation
18. Severe vision or hearing impairment that would prevent the participant from performing the psychometric tests accurately. This will be a clinical determination by the study physician without formal testing or audiometry Physician Evaluation
19. Olfaction component: current upper respiratory infection (patient tested as soon as this improves), current smoker > 1 pack daily (past smoking has been shown not to affect UPSIT scores, UPSIT score \< 12/40 (10 out of 40 is scored by chance in this multiple-choice test) indicating congenital anosmia. In the investigators' experience, less than 3% of cases are excluded for having one or more of these exclusionary criteria. If a patient is excluded from the olfaction component, the patient will still be eligible for the main protocol and all other study procedures. Patient Report/Physician Evaluation