Researchers have in recent years put forward contradictory evidence for and against a role for persistent infection, such as by herpesviruses, in neurodegeneration and the incidence of Alzheimer’s disease. The Alzheimer’s disease scientific community is in need of a good explanation as to why only some people with the known risk factors go on to develop the condition.
That disease incidence in fact depends on the burden and duration of persistent infection would be a convenient answer, if true. It is often the case that contradictory evidence means that better segmentation of the population of interest is required. Along these lines, researchers here suggest that infection is more of a contributing cause to Alzheimer’s disease in people with the APOE4 allele that confers a greater risk of Alzheimer’s disease. About a quarter of all people have one copy of APOE4.
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Several studies have suggested the implication of infectious agents in Alzheimer’s disease (AD) pathophysiology with herpes simplex virus type 1 (HSV-1) being one of the most investigated candidates. In fact, the implication of HSV-1 could potentially explain the location, chronology, and the type of damage described in AD. First, HSV-1 is a neurotropic virus with a particular tropism for the temporal cortex, as shown by the localization of lesions in HSV-1 encephalitis and postmortem studies highlighting the presence of HSV DNA in the brains of older adults. HSV-1 also has the ability to move from neurons to neurons, which could explain the progression of lesions to other brain areas.
Second, HSV-1, which remains in a latent state throughout life after primary infection, can periodically reactivate during a temporary immune decline. With advancing age, the development of a long-lasting immunosenescence may allow more frequent and/or more intense reactivations of the virus, thereby explaining the progressive and relatively late onset of AD. Finally, HSV-1 could be linked to genetic risk factors of AD, especially APOE4. The existence of such genetic susceptibility factors could explain why, despite a seroprevalence of ~80% in the elderly, some infected individuals remain “healthy carriers”, while others develop clinical consequences of the infection.
Our findings suggest an increased risk of AD in subjects infected by HSV. Infected subjects with an anti-HSV IgG level in the highest tercile (possibly reflecting more frequent reactivations over time) had lower hippocampal volume (HV) compared to uninfected subjects. Infected subjects presented also more microstructural alterations of the parahippocampal cingulum and fornix. Our results are also in favor of an interaction between being infected with HSV and APOE4 status regarding advanced markers of the disease (HV and then incidence of AD). Among APOE4 carriers, infected subjects presented lower HVs, although not significant, and had a two times higher risk of developing AD and a three times higher risk if their anti-HSV IgG level was in the highest tercile. Among APOE4 noncarriers, no associations were observed between HSV status and HV or incidence of AD.
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