Anti-viral treatment in Mild Cognitive Impairment (MCI) is a Phase II, placebo-controlled,
52-week trial using oral valacyclovir 4 g/day in 50 HSV seropositive, AD biomarker-positive,
amnestic mild cognitive impairment (MCI) patients (eMCI and lMCI). The trial will directly
address the long-standing viral etiology hypothesis of Alzheimer's disease (AD) which posits
that viruses, particularly the very common herpes simplex virus-1 (HSV1) and herpes simplex
virus-2 (HSV2), may be etiologic or contribute to the pathology of AD. This trial will
intervene at an earlier stage (MCI). We will compare the repurposed drug valacyclovir to
placebo in patients with amnestic MCI (eMCI and lMCI) in a randomized, double-blind, two-arm
parallel group 52-week pilot trial. Our Phase II trial will be the first antiviral drug trial
conducted in MCI.
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.This trial will intervene at an earlier stage (MCI).
In AD biomarker positive patients with Mild Cognitive Impairment (eMCI and lMCI) who test
positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir will
be compared at oral doses of 4 grams per day, to matching placebo in the treatment of 50
patients (25 valacyclovir, 25 placebo) in a randomized, double-blind, 52-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 52-week trial.
We will explore apolipoprotein E e4 genotype as a moderator, and changes in global clinical
status, viral antibodies and proteomic assays, AD signature of MRI regional and whole brain
cortical thinning, and plasma total tau, p-tau epitopes and neurofilament light (Nfl) protein
markers for neurodegeneration as exploratory hypotheses.
This innovative Phase II proof of concept trial clearly has exceptionally high reward
potential for the treatment of MCI.