# Anti-Viral therapy in Alzheimer's disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $2,372,211

## Abstract

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. We 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 g 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. 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 we
will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome measures. If this trial
is successful, we 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.

## Key facts

- **NIH application ID:** 9936129
- **Project number:** 5R01AG055422-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DAVANGERE P DEVANAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,372,211
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936129

## Citation

> US National Institutes of Health, RePORTER application 9936129, Anti-Viral therapy in Alzheimer's disease (5R01AG055422-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936129. Licensed CC0.

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