Alzheimer’s disease (AD) accounts for 60 to 70% of cases of dementia,1 with an estimated 5 million cases in the US currently. The number of cases in the US is expected to exceed 13 million by 2050,2 with over 105 million cases worldwide in the next 40 years.3 Efforts to develop effective pharmaceutical treatments have been futile4; Trials of medication purported to clear amyloid have, at times, been successful in reducing detectable amyloid, but they have entirely failed to improve cognitive function or slow its progressive decline.4,5
In addition to the hallmark pathological findings in AD, including amyloid plaques, neurofibrillary tangles, tau proteins, and neuronal degeneration, evidence of inflammation is often found.6,7 The DNA of herpes simplex virus 1 (HSV-1) has also been found to co-localize with amyloid plaques.8 This possibly spurious finding does not stand in isolation. Indeed, a recent research article documenting microbial infections in animal models of Alzheimer’s disease published in Science Translational Medicine9 by Deepak Kumar Vijaya Kumar, PhD, and colleagues and an editorial published in the Journal of Alzheimer’s Disease10 by an international consensus group of 33 physicians and scientists presents extensive research evidence from over 100 research studies and calls upon the neurological and medical communities to re-examine the bias against an infectious etiology for AD. Let’s explore the merit of this proposal.
A key postulate behind the causal link between an infectious agent and AD is the purported ability of viruses, such as HSV-1, to exist in the brain in a dormant or non-fulminant state for many years and, at some later point, reactivate. A model of this phenomenon is manifested by another member of the herpes family (varicella). Varicella infects most people as young children and causes chicken pox. In a portion of those so infected, the varicella virus takes up residence in the neurons of the spinal cord or dorsal root ganglia. Decades later, the virus reactivates and shingles is the result. Professor Ruth Itzhaki, MSc, PhD, MA and colleagues10 illustrate the increased likelihood of such reactivation following stress or decreased immune function.11
A second key postulate is that evidence of such silent infections actually exists in the brains of those afflicted with AD. Evidence of HSV-1 is indeed present in the brains of the elderly, both those with AD and those who are healthy.12 HSV-1 DNA was most prevalent in the temporal and frontal lobes of the brain — the very parts affected by AD.13 In the brains of patients with AD, 90% of the plaques examined contained HSV-1 DNA. In contrast, HSV-1 DNA was more randomly distributed in elderly controls with only 24% of the DNA associated with plaques (which are much fewer in elderly controls).13
A third key postulate is that exposure to an infectious agent increases the likelihood of AD. Luc Letenneur, PhD, and associates14 and Hugo Lovheim, MD, PhD, and associates15 independently published longitudinal large population (total n > 4,000) studies of the positive correlation between immunoreactivity to HSV-1 and Alzheimer’s disease. A recent report of the population of a small Pennsylvania town did not support an association between HSV-1 and AD.16 A strong positive correlation exists between positive HSV-1 antibody titers and cortical grey matter thinning.17
A fourth key postulate is that those who develop AD are in some way responding differently to the infection compared to those who do not. Remember, 34% of Americans have antibodies to HSV-1,18 but only approximately 12% have AD. Moreover, this difference would need to be such that it increased the risk of reactivation or neurovirulence. A recent independent meta-analysis showed the risk for AD was higher among those positive for herpes viruses. Indeed, the combination of the risk factor gene for AD, apolipoprotein ε4 gene (APOε4), and HSV-1 had an odds ratio of 2.71 for AD.19 Moreover, Professor Itzhaki and colleagues20 showed that the likelihood of being positive for HSV-1 DNA in the brain was much higher among patients who had the APOε4 gene. Examining this genetic association in animal models has furthered our understanding. Transgenic APOε4-positive mice infected with HSV-1 developed amyloid accumulations and neurofibrillary tangles (resembling AD) at a much denser level than similar mice which were not exposed to the HSV-1 virus.20 Evidence suggests that APOε4 increased the endocystosis of viral particles into cells.21 Multiple other AD-related genes have been implicated in the HSV-1 processes of infection, reactivation, and viral-gene transcription.22