Alzheimer's disease is characterized by the formation of beta-amyloid plaques and neurofibrillary tangles in the brains of affected individuals. These plaques build up, eventually blocking receptors in the synaptic gap. As neurons become disconnected from each other, they die. Stored memories fade. Researchers have searched for both genetic and environmental causes, finding
over 20 genetic loci linked to the disease. Researchers have classified several modes of inheritance for the disease, suggesting that many different loci throughout the genome can influence the amyloid pathway. Genome wide association studies of at risk families may reveal previously undiscovered risk factors. The most notorious currently known is APOE4, an isoform of APOE that differs from the protective APOE2 variation by two amino acids. The protein is important in catabolism of lipoproteins in the liver (Entrez Gene). Since 1980, some researchers have pointed to another potential cause of excessive amyloid plaque buildup, herpes simplex 1 (HSV1) (Middleton et. al). HSV1 has an ancient evolutionary relationship with man. It can insert its DNA into the human genome, frequently activating the inserted genes to replicate once again. The mechanisms with which the virus inserts itself into the human genome and controls the expression of its genes is a hot topic. HSV1 makes use of its host RNA polymerase to produce its mRNAs. HSV1's sporadic replication results in a constant battle with the immune system, producing side effects such as inflammation of the blood vessels. HSV1 has been linked to cardiovascular disease. The virus has been blamed for unexplained illnesses; a scapegoat in a sense. According to Wozniak, Mee, and Itzhaki (2009), HSV1 and the APOE4 isoform with increased lipoprotein binding potential interact to form amyloid plaques in Alzheimer affected brains.
In their 2009 paper, "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques," Wozniak et. al (2008) once again attempt to link HSV1 with beta amyloid plaques found in the brains of Alzheimer's diagnosed and "normal" deceased humans. They used "in situ" PCR coupled with immunohistochemistry or thioflavin S to detect HSV1 in amyloid deposits. They hypothesized that HSV1 alters APP processing and expression, a precursor to beta amyloid. They only used samples from six subjects in the experimental group and from five subjects in the control group. The APOE4 frequency of the experimental group was 58% while the APOE4 frequency of the control group was 0%. This concerns me because the samples for the experimental group came from APOE4 homozygotes or heterozygotes. Also, the experimenters failed to examine the brains of non-herpes infected subjects to eliminate the possibility that a normal amount of plaque builds up in even the brains of non-infected individuals. The structure of the paper is typical: a rundown of the beta amyloid and neurofibrillary tangle involved pathways and their unknown components followed by the implication of HSV1. Logically, the authors mention herpes simplex encephalitis, infection of the brain by HSV1, to stress the health risks of HSV1 infection and proximity to Alzheimer's affection regions. In their discussion, the authors admit that correlation of HSV1 and amyloid plaques does not mean causation.
In the above figure Wozniak et. al show samples from young, normal individuals and an unidentified "uninfected cell." However, they fail to produce a verified uninfected cell sample from an elderly individual. They do not present evidence that plaques are rarer in the brains of non-infected elderly humans than in infected elderly humans, nor do they distinguish between samples from APOE4 carriers and non carriers.
The MSNBC report, "Can you catch Alzheimer's disease?" appeals to pathos more than logos, inspiring fear and sympathy. It begins with an account of a young man Rich, whose girlfriend's father recently died from Alzheimer's. The man was not even related to him so he should not fear possesion of a risk allele. The article never implied he suffers from cold sores. Sorry to rush you McGraph, but please get to the facts. McGraph, author of the article, cites Ruth Itzhaki, Ph.D., who claims that 60% of Alzheimers cases could be caused by HSV1. She does not offer any evidence to support this statement. McGraph drops facts from various studies but in no way mentions them in context of a control. For example, he mentions that the researchers found HSV1 in 90% of amyloid plaques. The rate of HSV1 infection by that age is over 80%. The article turns into a sob story about how Itzhaki can not get research funding. Maybe she should work on those controls a bit. McGrady drops another fun fact: people who have the APOE4 gene and herpes are 15 times more likely to develop Alzheimer's than those who have neither. What about people who only have herpes and only have one or two copies of APOE4? Then, McGrady quotes Wozniak and Itzhaki to present to readers the so what? why do we care? Well, maybe...just maybe...a lifetime of antivirals that have not undergone a clinical trial for over a year of use will prevent HSV1 from infecting your brain and directly causing those amyloid plaques. We are also looking at an "epidemic" of Alzheimer's cases due to those baby boomers. What pests, spreading their epidemics. I would not call this scientific reporting at its best.
APOLIPOPROTEIN E4, 22K DOMAIN
Althought the Wozniak et. al (2008) may have not provided absolutely conclusive evidence of the link between HSV1 and Alzheimer's, they presented their data in a fair, concise manner. The MSNB story colloquialized the Wozniak et. al (2008) data and attempted to portray the disease as a spreadbale epidemic. The author hoped to create an atmosphere of sympathy, doubt, and fear to draw in readers, rather than factually present the data in a way the average reader could correctly interpret.
Wozniak et. al (2008) have not released further evidence in the form of more samples or better controls to support their claim that HSV1 causes Alzheimer's. Alzheimer's and its association with HSV1 needs to be examined from a genome-wide and evolutionary standpoint. What types of proteins could HSV1 or immune byproducts influence? How exactly does HSV1 enter the brain, how does its DNA interact with the host genome, and how does its presence influence the expression of host genes? Researchers should sequence infected brain cells to categorize viral DNA, perform in situ hybridization, run arrays, and quantify normal RNA expression in APOE4 knockout mice, HSV1 APOE4 knockout mice, HSV1 mice, and APOE4 mice.