A group from Italy’s University of Bologna report that genetic defects in antimicrobial defense mechanisms can leave some individuals vulnerable to sub-clinical infections that lead to cognitive decline as they age. They found variations in specific antiviral genes that correlate with HHV-6 DNA levels in brain tissue and blood from patients with Alzheimer’s disease.
The group found that several genetic factors involved in regulating antiviral response correlate with both Alzheimer’s Disease (AD) and HHV-6 DNA positivity: interferon λ3 (also known as IL-28B) TT genotype, Mediator 23 complex (Med 23) GG genotype and interferon regulatory factor 7 (IRF7).
In addition, EBV and HHV-6 IgG antibody levels were increased in Alzheimer’s Disease (AD) patients with an interferon regulatory factor IRF7 GG genotype. The authors conclude that both EBV and HHV-6 appear to be risk factors for AD in genetically susceptible elderly.
Of interest, the authors found that in a subset of Alzheimer’s patients positive for one or more of these three variants, 87.5% had HHV-6 DNA in their white blood cells compared to 12.5% of controls who were positive for one of the three variants but did not develop Alzheimer’s.
In an earlier paper, the same group showed that HHV-6 DNA was found in the blood of 23% of AD patients but only 4% of controls in 150 elderly patients who were followed for five years. HHV-6 antibody titers were elevated in 22% of those who developed AD, vs. only 4.4% who remained cognitively healthy (Carbone 2014).
According to the authors, Med 23 upregulates interferon λ by interacting with IRF7. Originally identified because of its role in EBV infection, IRF7 is now recognized as the crucial regulator type I interferons. They point out that recent studies suggest that interferon –λ exerts its antiviral activity in vivo by stimulation the immune system to increase NK and T cell cytotoxicity.
Ruth Itzhaki of University of Manchester, who first proposed herpes simplex involvement in AD in 1991, has called for a trial of antivirals and immune modulator such as intravenous immunoglobulin to treat AD patients. Her studies have generated strong support for a role for HSV-1 in AD, with HSV-1 levels appearing at much higher levels in AD brains vs. controls and the HSV-1 is localized in amyloid plaques. APOE –ε4 transgenic mice infected with HSV-1 show greater viral damage (Itzhaki 2014). Some investigators even suggest that amyloid-beta production is an “antimicrobial” response to viral infection (Soscia 2010).
HHV-6 is highly neurotropic and has been shown to cause delirium and cognitive problems in stem cell transplant patients (Zerr 2011) as well as limbic encephalitis (Ogata 2015). Active or reactivated HHV-6B has been found in one third of infants with febrile status epilepticus, and is the only virus found in significant amounts in the brain resections from patients with refractory epilepsy (Kawamura 2015).
The group led by Federico Licastro in the Department of Experimental, Diagnostic and Specialty Medicine in Bologna, call for increased studies in a larger cohort.
For more information, read the full paper.