Seropositivity to Herpes Simplex Virus Antibodies and Risk of Alzheimer's Disease: A Population-Based Cohort Study

INSERM, U897, Bordeaux, France.
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(11):e3637. DOI: 10.1371/journal.pone.0003637
Source: PubMed


Herpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer's Disease (AD) notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-based cohort of elderly subjects living in the community.
Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years.
During the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR = 2.55; 95% CI [1.38-4.72]), although no significant increased risk was observed in IgG-positive subjects (HR = 1.67; 95%CI [0.75-3.73]). No modification effect with APOE4 status was found.
Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD.

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    • "Numerous experimental findings suggest the implication of HSV-1 infection in AD pathogenesis [see recent reviews by Itzhaki, 2014; Piacentini et al., 2014] and there is growing evidence that other herpesviruses might be involved. The presence of IgM anti- HSV antibodies (recognizing HSV-1 and HSV-2 antigens) in serumda marker of HSV reactivationdwas found to be correlated with an increased risk of developing AD (Letenneur et al., 2008; Lovheim et al., 2014). Recently, EBV and human herpes virus 6 DNA positivity, along with CMV and EBV IgG plasma levels, were also associated with cognitive decline and progression to AD in the elderly (Carbone et al., 2014). "
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    ABSTRACT: Herpes simplex virus (HSV) types 1 and 2 are neurotropic viruses that establish lifelong latent infections in neurons. Mounting evidence suggests that HSV-1 infection is involved in the pathogenesis of Alzheimer's disease (AD). The relationships between other herpesvirus infections and events associated with neurodegeneration have not, however, been extensively studied. The present work reports that HSV-2 infection leads to the strong accumulation of hyperphosphorylated tau and the amyloid-β peptides Aβ40 and Aβ42 (all major pathological hallmarks of AD) in human SK-N-MC neuroblastoma cells. Infection is also associated with a marked reduction in the amount of Aβ40 secreted and in the proteolytic fragments of the amyloid-β precursor protein (APP) (secreted APPα and the α-C-terminal fragment). These results indicate that HSV-2 infection inhibits the nonamyloidogenic pathway of APP processing and impairs Aβ secretion in these cells. In addition, HSV-2 induces the accumulation of intracellular autophagic compartments containing Aβ due to a failure in the late stages of autophagy. To our knowledge, this is the first report to show that HSV-2 infection strongly alters the tau phosphorylation state, APP processing, and autophagic process in human neuroblastoma cells, leading to the appearance of AD-like neurodegeneration markers. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Neurobiology of aging
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    • "Lycke and coworkers first described an increased prevalence of anti-HSV antibodies among persons with dementia [2], and a few years later Ball presented a hypothesis involving HSV as a cause of Alzheimer's disease (AD) based on similarities between HSV encephalitis and AD [3]. Recent epidemiological cohort studies by ourselves, and others, have indeed identified an increased risk of AD following HSV reactivation, as measured by the presence of anti-HSV immunoglobulin M (IgM) antibodies [4] [5]. A possible connection is further supported by studies demonstrating the detection of HSV1 within brain tissue from patients with AD and specifically within amyloid plaques [6] [7] [8] [9] [10], and by the finding that HSV1 infection can induce amyloid beta production and tau hyperphosphorylation in cultured neural cell types [11] [12] [13] [14] [15] [16] [17]. "
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    ABSTRACT: Background Herpes simplex virus (HSV) is thought to play an etiological role in the development of Alzheimer's disease (AD). Methods Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years) and 360 age- and sex-matched dementia-free controls, taken on average 9.6 years before AD diagnosis, were analyzed for anti-HSV antibodies (immunoglobulin G, IgG, and immunoglobulin M, IgM) by enzyme-linked immunosorbent assays. Results In the complete sample group, the presence of anti-HSV IgG and IgM antibodies did not increase the risk of AD significantly (odds ratio (OR) 1.636, P = .069 and OR 1.368, P = .299, respectively). In cases with 6.6 years or more between plasma sampling and AD diagnosis (n = 270), there was a significant association between presence of anti-HSV IgG antibodies and AD (OR 2.250, P = .019). Conclusion Among persons with a follow-up time of 6.6 years or more, HSV infection was significantly associated with AD.
    Full-text · Article · Oct 2014 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    • "The first study on anti-HSV IgM, by Letenneur et al. (2008), revealed that elderly subjects who were IgM-positive were far more likely to develop dementia within the following 14 years than were those who were IgG- but not IgM-positive, thus supporting the concept that reactivation of the virus leads eventually to dementia. Subsequently, Féart et al. (2011) found that high IgM levels, but not IgG levels, are associated with low plasma levels of Aβ1-40 and 1-42—which are considered to be biomarkers of the disease, in that their decrease might reflect accumulation of Aβ in brain cells (and hence a reduction in plasma level). "
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    ABSTRACT: Abstract HSV1, when present in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE), has been implicated as a major factor in AD. It is proposed that virus is normally latent in many elderly brains but reactivates periodically (as in the peripheral nervous system) under certain conditions, for example stress, immunosuppression, and peripheral infection, causing cumulative damage and eventually development of AD. Diverse approaches have provided data that explicitly support, directly or indirectly, these concepts. Several have confirmed HSV1 DNA presence in human brains, and the HSV1-APOE-ε4 association in AD. Further, studies on HSV1-infected APOE-transgenic mice have shown that APOE-e4 animals display a greater potential for viral damage. Reactivated HSV1 can cause direct and inflammatory damage, probably involving increased formation of beta amyloid (Aβ) and of AD-like tau (P-tau) - changes found to occur in HSV1-infected cell cultures. Implicating HSV1 further in AD is the discovery that HSV1 DNA is specifically localised in amyloid plaques in AD. Other relevant, harmful effects of infection include the following: dynamic interactions between HSV1 and amyloid precursor protein (APP), which would affect both viral and APP transport; induction of toll-like receptors in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivation of the virus in brain. Several epidemiological studies have shown, using serological data, an association between systemic infections and cognitive decline, with HSV1 particularly implicated. Genetic studies too have linked various pathways in AD with those occurring on HSV1 infection. In relation to the potential usage of antivirals to treat AD patients, acyclovir (ACV) is effective in reducing HSV1-induced AD-like changes in cell cultures, and valacyclovir, the bioactive form of ACV, might be most effective if combined with an antiviral that acts by a different mechanism, such as
    Full-text · Article · Aug 2014 · Frontiers in Aging Neuroscience
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