"The Viral Hypothesis of Alzheimer's Disease: Time to put it to the test!" by Steven P. LaRosa, M.D.

Alzheimer’s disease (AD) was estimated to affect 35.5 million people worldwide in 2010 and is expected to affect 115.4 million people by 2050. Approximately 10% of people over 65 are affected and 50% of population > 85 are affected. The currently approved drugs provide minimal benefit. The benefit of experimental drugs observed in Phase II clinical trials has been followed by resounding failures in adequately powered Phase III clinical trials. Even the results of the highly publicized Biogen study have significant questions associated with it. It is quite clear that a new strategy must be entertained and tested.

Four members of the Human Herpes Virus family have been associated with development of Alzheimer’s disease; HSV-1, VZV, HHV-6A, and HHV-7. HSV-1 is capable in vitro leading to the production the Beta amyloid protein found in senile plaques and phosphorylating tau protein seen in neurofibrillary tangles seen in Alzheimer’s, a  phenomenon that can be blocked by co-incubating with acyclovir. Studies by Eimer et al in 5XFAD mice which hyperproduce Beta amyloid indicate that amyloid is elaborated rapidly following challenge with HSV-1 and is protective. This finding would indicate that amyloid is performing appropriately as an ancient immune protein to control infection and that repeated HSV-1 exposure may be the fuel to the amyloid build-up of Alzheimer’s.  Indeed, reactivation of HSV-1 infection as indicated by the presence of HSV-IgM antibodies in the setting of HSV IgG seropositivity has been associated with a 2-2.5X increase in Alzheimer’s disease. A recent retrospective study from the Taiwan National Health Insurance database compared 8362 patients greater than 50 with newly diagnosed HSV-1 infection to 25,086 sex and age- matched controls. HSV infection was associated with a 2.5 fold increased risk of dementia. A 90% reduction in the development of dementia was observed in the 7215 patients with new HSV infection who received anti-herpetic agents compared to the 1147 patients with new HSV infection who did not receive treatment. Similar but less dramatic findings were observed in individuals >50 with zoster (VZV), where infection was associated with a hazard ratio of 1.1 and treatment with an anti-herpetic medication was associated with a 45% reduction in the development of dementia (both statistically significant).

HHV-6A and HHV-7, which infect over 90% of humans over a lifetime, have recently been associated with Alzheimer’s disease. In the study by Eimer and colleagues HHV-6A exposure led to elaboration of Beta amyloid within 48 hours in 3D neuronal cell cultures. Fibrillization around the virus occurred with prevention of infection. In a study by Readhead and colleagues looking at brain samples from 3 independent cohorts, HHV-6A and HHV-7 were found in increased abundance in Alzheimer’s brains. This was not the case in other causes of neurodegeneration. Specific HHV-7 and HHV-6A gene regions were associated with Clinical Dementia Rating score and plaque density. Additionally, HHV-6A was associated with regulation of genes involved in processing of amyloid precursor proteins. Finally, HHV-6A levels had a negative correlation with neuronal cell fraction.

 Given the prevalence of infection with Human Herpes viruses in the population, an attempt must be made to explain the discordance with the number of Alzheimer’s disease cases. The most likely explanations involve host-genetics and host –pathogen interactions. Other than age the major risk factor for Alzheimer’s disease is the presence of Apolipoprotein E allele epsilon₄ (ApoEe₄). Humans can have zero, one or two copies of ApoEe₄. Approximately 10% of the population is homozygous for APOEe₄ with a 12X increased risk for AD while 49% are heterozygous associated with a 2-3X increased risk of AD. In one study the presence of a least one allele for ApoEe₄ allele and HSV seropositivity was associated with AD in brain samples but not either factor alone. In an acute mouse infection model ApoEe₄ homozygous mice had 13.6X higher levels of brain HSV-1 DNA compared with knockout mice. Similarly, the more ApoEe₄ copies, the more AD in humans, and the more HHV-6A/B particles are found in the human brain. Additional genes that are associated with both risk of AD and susceptibility to viral infections include PILRA and ITGB3.

So what would be the next steps in testing the viral hypothesis of Alzheimer’s disease? To move from association to causality a randomized, placebo controlled trial of anti-viral in patients with early Alzheimer’s disease would need to be performed. The only agent with anti-viral activity against HHV-6A and HHV-7 in addition to HSV-1 and VZV is the experimental EPB-348 (Valomaciclovir). Based on the above data subjects would be included if they have evidence of HSV-reactivation (HSV-IgM seropositivity). The population could be enriched with those with at least one ApoEe4 allele or subgroup analysis could be performed in genetic traits associated with AD and viral infection to search for differential response to therapy. Patients would be followed out 78 weeks to look for a clinically meaningful slower decline in a measure of cognition and function such as the CDR-sum of boxes score.