January 28, 2007
People who carry a gene that raises the risk for Alzheimer's disease in old age may also be more prone to infection with the cold sore virus. Though much more research is needed, the findings, published online in the medical journal Neurobiology of Aging, suggest there may be some kind of link between the cold sore virus and the onset of Alzheimer's disease.
The gene, called ApoE4, is a known risk factor for Alzheimer's disease. People who inherit the gene are at increased risk for Alzheimer's in old age. However, not everyone who carries the ApoE4 gene will suffer from memory loss and other symptoms of Alzheimer's as they grow old.
Scientists suspect that the gene may predispose people to more virulent infection with the virus that produces cold sores, the small, raw, open sores that commonly appear on the outside edges of the lips. Also referred to as fever blisters, cold sores are caused by the type 1 herpes simplex virus, called HSV-1. It is distinct from the type 2 herpes virus (HSV-2) that more commonly produces genital herpes. HSV-1 infects more than 80 percent of Americans.
Most of the time, the herpes virus remains sequestered in nerve cells and does not cause symptoms. It can produce periodic flare-ups, especially during times of stress, illness or fatigue. It is possible that the ApoE4 gene somehow allows the herpes virus to be more active in the brain. The current findings, from researchers at the University of Rochester Medical Center in New York, show that the particular form of the gene that puts people at risk for Alzheimer's also creates a fertile environment for herpes in the brain. It thereby allows the virus to be more active than other forms of the ApoE gene permit. The findings are based on measurements of the activity levels of the herpes virus in the brains of mice with different forms of the human ApoE gene.
Scientists have known for more than 15 years that the ApoE4 gene is a player in Alzheimer's disease, but the idea that it works in concert with the herpes virus is new. "This work raises the question whether herpes, in concert with ApoE4, increases the risk of Alzheimer's disease," says study leader Howard Federoff, M.D., Ph.D. "The data suggests that ApoE4 may support the ability of HSV to be a more virulent pathogen." The Herpes-Alzheimer's Connection Past studies have suggested there may be a connection between herpes and Alzheimer's, though more study in this area is needed. Ruth Itzhaki of the University of Manchester in the U.K. has shown that people with Alzheimer's who carry the ApoE4 gene have more herpes DNA in the brain regions that are affected by Alzheimer's, compared to Alzheimer's patients who are also infected with the herpes virus but who have a different form of the ApoE gene. She has also shown that people with the ApoE4 version of the gene who are infected with herpes are more likely to get Alzheimer's disease than people infected with herpes who have a different form of the ApoE gene, or than people who have the ApoE4 gene but who don't have herpes. However, carriers of the ApoE4 gene are already known to be at greater risk for Alzheimer's.
Other scientists have found that a herpes infection is active more often causing the telltale cold sores around the mouth in the 25 percent of people who have a copy of the ApoE4 gene. In other words, people who are frequently troubled by cold sores are more likely to have the gene that makes them more vulnerable to Alzheimer's disease.
Researchers at Rochester focused on the brain cells of mice with different forms of the ApoE gene. They looked at four groups of mice: Some had ApoE3, which is what the majority of people carry; some had ApoE4, which in people makes them more likely to get Alzheimer's; some had ApoE2, which makes people less likely to get Alzheimer's; and some had no ApoE gene at all.
The team found that the virus infiltrates brain cells about the same no matter which gene is involved. But they found that the subsequent activity level of the virus generally mirrored the Alzheimer's-causing potential of the gene. They found that in animals with the ApoE4 gene, the virus is less likely to be in the quiet, latent stage of its life cycle, and compared to animals with non-ApoE4 genes, more likely to have the virus in its active state. In animals with the ApoE2 gene, the virus was less active.
The ApoE gene is well known to Alzheimer's researchers. The gene normally plays a role in ferrying cholesterol around the body. Researchers have found several ways in which the gene might make a person vulnerable to developing Alzheimer's. In people with the ApoE4 gene, brain cells don't seem to recover as well from injury, and the cells don't form new connections as well as cells equipped with either ApoE2 or ApoE3. Other scientists have shown that the gene plays a role in clearing excess beta-amyloid, a toxic protein that builds up in the brains of those with Alzheimer's. "Just how ApoE4 makes people vulnerable to Alzheimer's disease isn't resolved at all," said Federoff. "It may be that it works in multiple ways."
More research is required to untangle the role of herpes and other agents in the onset of Alzheimer's disease, an ailment that afflicts some 4.5 million Americans, and many more worldwide. For more on Alzheimer's and the search for a cure, visit www.ALZinfo.org.
University of Rochester Medical School, Press Office. R.M. Miller and H.J. Federoff: "Isoform-specific effects of ApoE on HSV immediate early gene expression and establishment of latency." Neurobiology of Aging, online, November 13, 2006.