Anti-viral Therapy in Alzheimer's Disease

Many viruses are latent for decades before being reactivated in the brain by stress, immune
compromise, or other factors. After the initial oral infection, herpes simplex virus-1 (HSV1)
becomes latent in the trigeminal ganglion and can later enter the brain via retrograde axonal
transport, often targeting the temporal lobes.

HSV1 can also enter the brain via olfactory neurons directly. HSV1 (oral herpes) and HSV2
(genital herpes) are known to trigger amyloid aggregation and their DNA is commonly found in
amyloid plaques. Anti-HSV drugs reduce Aβ and p-tau accumulation in brains of infected mice.
HSV1 reactivation is associated with tau hyperphosphorylation in mice and may play a role in
tau propagation across neurons. In humans, recurrent reactivation with newly produced HSV1
particles, 'drop by drop,' may produce neuronal damage and eventually lead to
neurodegeneration and Alzheimer's disease (AD) pathology, partly due to effects on amyloid
and tau. Clinical studies show cognitive impairment in HSV seropositive patients in different
patient groups and in healthy adults, and antiviral treatments show robust efficacy against
peripheral HSV infection. The study team will conduct the first-ever clinical trial to
directly address the long-standing viral etiology hypothesis of AD which posits that viruses,
particularly the very common HSV1 and HSV2, may be etiologic or contribute to the pathology
of AD. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the
generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral
doses of 2 to 4 grams per day to matching placebo in the treatment of 130 patients (65
valacyclovir, 65 placebo) in a randomized, double-blind, 78-week Phase II proof of concept
trial. Patients treated with valacyclovir are hypothesized to show smaller decline in
cognition and functioning compared to placebo, and, using 18F-Florbetapir PET imaging, to
show less amyloid accumulation than placebo over the 78-week trial. Through the use of tau
PET imaging with the tracer 18F-MK-6240 at baseline and 78 weeks, patients treated with
valacyclovir are hypothesized to show smaller increases in 18F-MK-6240 binding than patients
treated with placebo from baseline to 78 weeks. Apolipoprotein E genotype at baseline, as
well as changes in cortical thinning on structural MRI, olfactory identification deficits,
and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory
analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed
to establish the degree of CNS penetration of valacyclovir in mild AD, and the investigators
will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome
measures. If this trial is successful, the investigators will apply for funding to conduct a
larger, multicenter, Phase III study using a study design that will be informed by the
results of this Phase II trial. This innovative Phase II proof of concept trial clearly has
exceptionally high reward potential for the treatment of AD.

Inclusion Criteria:

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 highdose benzodiazepines), will be permitted throughout the
trial. Doses of these medications will need to be stable for at least 2 months 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.

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

20. Clinical judgment that past lifetime radiation exposure is extensive enough to make
exposure to PET scans in the current study inadvisable.

Clinical judgment of the evaluating study physician

21. Serum vitamin B12 levels below the normal range. Physician Evaluation/Laboratory
Report