Re-Examining Infectious Causes of Alzheimer’s Disease

A fifth key postulate is that a demonstrable mechanism of action must exist for HSV-1 to cause, induce, or increase the pathophysiological processes associated with AD. Tissue culture studies demonstrated HSV-1 infection induced immortalized neurons to produce excess amyloid protein.23 Work in cultured cells revealed that HSV-1 alters the processing of the precursor proteins leading to amyloid,24,25 resulting in abnormal accumulations of amyloid. Moreover, HSV-1 increases the formation of a second abnormal protein, tau, which forms the neurofibrillary tangles commonly found in AD.26. Similarly, mice infected with HSV-1 developed an excessive accumulation of amyloid protein in their brains, mimicking AD.23 Of great clinical interest, currently available antiviral medications, such as acyclovir, have been shown to slow, halt, or reverse the accumulation of some of amyloid and tau proteins when applied to infected neurons in culture.27

Professor Itzhaki and colleagues provide many more points of evidence in the short, but pointed editorial.10 The question is: What is our bias? What has prevented the serious evaluation of this infectious etiology of AD? A perusal of this year’s Alzheimer’s Association national meeting agenda reveals no sign of HSV-1 or other possible infectious contributors to the pathogenesis of AD. In an age when vaccines are used to prevent virally-induced cancers (cervical cancer and human papilloma virus), when antibiotics are used to treat bacterially-induced stomach ulcers (helicobacter pylori), and when parasites have been shown to be linked to suicide (toxoplasmosis), it seems odd that there is such resistance to this possible mechanism. I am reminded how John Lykoudis was penalized in 1950s Greece for treating ulcers with antibiotics28 and how Barry Marshall had to drink a vial of H. pylori, giving himself gastritis and ulcers, to prove the causal relationship between the bacterium and stomach ulcers.29

Still, the argument can be made that most people have been exposed to, and make antibodies to HSV-1. It is oft-reported that “up to 90%” of people have HSV-1 immunoreactivity. In fact, the incidence of HSV-1 in the US is approximately 34%.17 At my own clinic, I have found that only 24% of my patients had antibodies to HSV-1. In contrast, it has long been shown that 60% or more of elderly patients have latent HSV-1 DNA.30 It would seem that age plays a role in CNS access and in progression of latent HSV-1 infection. This seems reasonable when one considers the weakening of the immune system with age, by depletion of natural killer cells, shifts in cytokines, and immune exhaustion.31,32 Also, the HSV-1 virus is often localized to the neurons of the trigeminal ganglion. These bipolar primary sensory neurons not only innervate the meninges, but their central axon innervates the brainstem trigeminal nuclei.33 Over time, an incremental increase in the numbers of viral particles crossing into the CNS may occur.

With a mountain of epidemiological, animal, tissue culture, and pathological data supporting a link between HSV-1 and AD, it would seem reasonable to fund studies of how preventing or eliminating HSV-1 might change the course or incidence of AD. Studies of HSV-1 vaccines have been promising. Mice treated with an experimental vaccine can be exposed to HSV-1 without the virus establishing persistent latent infections, unlike unvaccinated mice.34 Current antivirals such as valacyclovir are safe and effective in curbing the activity of HSV-1 and other Herpes-family viruses.35,36

Why not fund and conduct a trial of long-term antivirals in those at high risk for developing AD? Is the bias justified or does it reflect a resistance, either conscious or unconscious, against the change from a neurodegenerative model to an infectious model. We each must ask ourselves: What is our resistance and from where does it come?

Theodore Henderson, MD., PhD, is a psychiatrist in Denver, Colo., who specializes in the diagnosis of complex adult, child, and adolescent psychiatric cases.

For references, please see next page.