Infections, Vaccinations, and Risk of Alzheimer's Disease (AD)/Dementia: Probable Involvement of Reactivated Herpes Simplex Virus Type 1.

Infections are associated with cognitive decline and increased risk of AD/dementia (Sochocka M, Zwolinska K, Leszek J. Curr Neuropharmacol 15:996-1009, 2017; Ou YN, Zhu JX, Hou XH, Shen XN, Xu W, Dong Q, et al. J Alzheimers Dis 75:299-309, 2020; Sipilä PN, Heikkilä N, Lindbohm JV, Hakulinen C, Vahtera J, Elovainio M, et al. Lancet Infect Dis 21:1557-1567, 2021; Damiano RF, Guedes BF, de Rocca CC, de Padua Serafim A, Castro LHM, Munhoz CD, et al. Eur Arch Psychiatry Clin Neurosci 272:139-154, 2022), and some studies have shown that vaccinations, such as BCG, against a variety of infections decrease the risk. Several reports have described an association of varicella zoster virus (VZV) with AD, and in an epidemiological study, we found that shingles, a disease caused by VZV, conferred a small increased AD/dementia risk, while vaccination against the disease led to a greatly decreased risk - subsequently confirmed by others (Lophatananon A, Mekli K, Cant R, Burns A, Dobson C, Itzhaki R, Muir K, BMJ Open 11:e045871, 2021a; Lehrer S, Rheinstein PH. In Vivo 35:3271-3275, 2021; Scherrer JF, Salas J, Wiemken TL, Hoft DF, Jacobs C, Morley JE. PLoS One 16:e0257405, 2021).

Dementia, infections and vaccines: 30 years of controversy.

This paper reports the proceedings of a virtual meeting convened by the European Interdisciplinary Council on Ageing (EICA), to discuss the involvement of infectious disorders in the pathogenesis of dementia and neurological disorders leading to dementia. We recap how our view of the infectious etiology of dementia has changed over the last 30 years in light of emerging evidence, and we present evidence in support of the implication of infection in dementia, notably Alzheimer's disease (AD). The bacteria and viruses thought to be responsible for neuroinflammation and neurological damage are reviewed. We then review the genetic basis for neuroinflammation and dementia, highlighting the genes that are currently the focus of investigation as potential targets for therapy. Next, we describe the antimicrobial hypothesis of dementia, notably the intriguing possibility that amyloid beta may itself possess antimicrobial properties. We further describe the clinical relevance of the gut-brain axis in dementia, the mechanisms by which infection can move from the intestine to the brain, and recent findings regarding dysbiosis patterns in patients with AD. We review the involvement of specific pathogens in neurological disorders, i.e. SARS-CoV-2, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV1), and influenza. Finally, we look at the role of vaccination to prevent dementia. In conclusion, there is a large body of evidence supporting the involvement of various infectious pathogens in the pathogenesis of dementia, but large-scale studies with long-term follow-up are needed to elucidate the role that infection may play, especially before subclinical or clinical disease is present.

The Alzheimer's Disease Chronicles: Will Evidence Triumph Over Adversity?

Herpes simplex virus type 1 (HSV1) infects most humans and remains lifelong in the body in latent form within the PNS. The virus can be reactivated by stress, immunosuppression etc, and in some people it then causes cold sores.

Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts.

Support for the concept that herpes simplex virus type 1 (HSV1), when present in the brains of apolipoprotein E-ε4 carriers, is a major risk for Alzheimer's disease (AD) is increasing steadily, with over 120 publications providing direct or indirect evidence relevant to the hypothesis. No articles have contested the concept, apart from 3 published 13-18 yr ago. This review describes very recent studies on the role of HSV1 but refers also to older studies that provide background for some lesser-known related topics not covered in other recent reviews; these include the relevance of herpes simplex encephalitis and of epilepsy to AD, the action of IFN, and the possible relevance of the different types of DNA damage to AD-in particular, those caused by HSV1-and mechanisms of repair of damage. New epidemiologic data supporting previous studies on mild cognitive impairment and progression to AD are reviewed, as are those examining the relationship between total infectious burden (additive seropositivity to various microbes) and cognition/AD. The latter indicates the involvement of HSV1 and cytomegalovirus (and the necessity of taking into account any marked differences in sensitivity of antibody detection). Recent studies that provide further support for the occurrence of repeated reactivation of latent HSV1 in the brain in AD pathogenesis are also discussed.-Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts.

COVID-19 and Alzheimer's Disease: What Is the Connection?

Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of AD.

Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1.

BACKGROUND: Varicella zoster virus (VZV) has been implicated in Alzheimer's disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain. OBJECTIVE: To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected with HSV-1. METHODS: We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and sought the presence of AD-related phenotypes such as amyloid-ß (Aß) and P-tau accumulation, gliosis, and neuroinflammation. RESULTS: Cells infected with VZV did not show the main AD characteristics, Aß and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZV's action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aß and P-tau accumulation. CONCLUSION: Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in AD/dementia via reactivation of HSV-1 in brain.

Investigation of the association between the antibody responses to neurotropic viruses and dementia outcomes in the UK Biobank.

The causes that trigger the onset of dementia are still unknown. Recently there has been an increasing interest in the possible role of infectious agents in the brain in the pathogenesis of this condition. Amongst the viruses, members of the Herpesviridae family, namely herpes simplex virus-1 (HSV1), cytomegalovirus (CMV), human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7) and varicella zoster virus (VZV) have been suggested as potential causes of the disease. However, the relative importance of these and other viruses in contributing to dementia remains unclear. We evaluated the association between seropositivity status of all viruses available in a large, population-based dataset (the UK Biobank) and dementia risk in an unbiased way. Of the 15 viruses investigated, our results showed a statistically significant increase of dementia risk associated only with HSV1 seropositivity (OR 2.14, 95% C.I. 1.21-3.81). However, by combining the data we found that seropositivity for 4 viruses (HSV1, HHV6, HHV7 and VZV) also significantly increases the risk of dementia (OR = 2.37, 95% C.I. 1.43-3.92). These four viruses have been described previously as neurotropic viruses. Our results provide support for a role for neurotropic viruses in the pathology of dementia.

Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer's Disease (AD); Underwhelming Evidence against.

This review describes investigations of specific topics that lie within the general subject of HSV1's role in AD/dementia, published in the last couple of years. They include studies on the following: relationship of HSV1 to AD using neural stem cells; the apparent protective effects of treatment of HSV1 infection or of VZV infection with antivirals prior to the onset of dementia; the putative involvement of VZV in AD/dementia; the possible role of human herpes virus 6 (HHV6) in AD; the seemingly reduced risk of dementia after vaccination with diverse types of vaccine, and the association shown in some vaccine studies with reduced frequency of HSV1 reactivation; anti-HSV serum antibodies supporting the linkage of HSV1 in brain with AD in APOE-ε4 carriers, and the association between APOE and cognition, and association of APOE and infection with AD/dementia. The conclusions are that there is now overwhelming evidence for HSV1's role-probably causal-in AD, when it is present in brain of APOE-ε4 carriers, and that further investigations should be made on possible prevention of the disease by vaccination, or by prolonged antiviral treatment of HSV1 infection in APOE-ε4 carriers, before disease onset.

Antivirals Against SARS-CoV2: Relevance to the Treatment of Alzheimer's Disease.

A recent study in vitro has shown that a sulphated polysaccharide, a type of fucoidan, has potent antiviral activity against SARS-Cov2. If the antiviral action were successful also for COVID-19 patients, it would be enormously valuable against not only acute disease but also long-term mental effects, which might include Alzheimer's disease (AD). In a trial of AD patients, the apparent success of treatment with a polysaccharide, GV971, was suggested to result from antiviral action against herpes simplex virus type 1 (HSV1) in brain, a pathogen strongly implicated in AD, and that sulphation of GV971, making it fucoidan-like, might increase its putative antiviral action. These data indicate that treatment of AD patients might be very effective using valacyclovir, a conventional antiviral, which inhibits viral replication, together with a fucoidan, which blocks virus entry into cells.

Hypothesis: Does the Apparent Protective Action of Green Valley's Drug GV971 Against Cognitive Decline Result from Antiviral Action Against Herpes Simplex Virus Type 1 in Brain?

There has been much interest in the clinical trial of GV972 for treatment of Alzheimer's disease in that the data have indicated that the compound is protective against cognitive decline. This effect has been attributed to a remodelling of the gut microbiota. I suggest that the effect might be caused by an antiviral action of GV971 against herpes simplex virus type 1 in brain, which many studies have strongly implicated as having a major role in Alzheimer's disease. The antiviral action of GV971 is proposed on the basis that it is an acidic polysaccharide consisting of linear sodium oligomannurarate molecules of a range of sizes, derived from brown algae. Marine-derived polysaccharides are well known for possessing various bioactivities, including antiviral and antibacterial properties.

Do infections have a role in the pathogenesis of Alzheimer disease?

The idea that infectious agents in the brain have a role in the pathogenesis of Alzheimer disease (AD) was proposed nearly 30 years ago. However, this theory failed to gain substantial traction and was largely disregarded by the AD research community for many years. Several recent discoveries have reignited interest in the infectious theory of AD, culminating in a debate on the topic at the Alzheimer's Association International Conference (AAIC) in July 2019. In this Viewpoint article, experts who participated in the AAIC debate weigh up the evidence for and against the infectious theory of AD and suggest avenues for future research and drug development.

Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1.

Neurofibrillary tangles are one of the main neuropathological features of Alzheimer's disease (AD) and are composed of abnormally phosphorylated forms of a microtubule-associated protein called tau. What causes this abnormal phosphorylation is unknown. Our previous studies have implicated herpes simplex virus type 1 (HSV1) as an etiological agent in AD, and so we investigated whether infection with this virus induces AD-like tau phosphorylation. Here we demonstrate that HSV1 causes tau phosphorylation at several sites, including serine 202, threonine 212, serine 214, serine 396 and serine 404. In addition, we have elucidated the mechanism involved by showing that the virus induces glycogen synthase kinase 3beta and protein kinase A, the enzymes that cause phosphorylation at these sites. Our data clearly reveal the importance of HSV1 in AD-type tau phosphorylation, and support the case that the virus is a cause of the disease. Together with our previous data, our results point to the use of antiviral agents to slow the progression of the disease.

Herpes simplex virus type 1 in Alzheimer's disease: the enemy within.

Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet its causes and that of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor - the type 4 allele of the apolipoprotein gene, a known susceptibility factor - is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are also discussed. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.

Herpes simplex virus type 1 and Alzheimer's disease: the autophagy connection.

The causes of Alzheimer's disease (AD) and of the characteristic pathological features - amyloid plaques and neurofibrillary tangles - of AD brain are unknown, despite the enormous resources provided over the years for their investigation. Indeed, the only generally accepted risk factors are age, Down syndrome, carriage of the type 4 allele of the apolipoprotein E gene (APOE-epsilon 4), and possibly brain injury. Following the authors' previous studies implicating herpes simplex virus type 1 (HSV1) in brain of APOE-epsilon 4 carriers as a major cause of AD, the authors propose here, on the basis of their and others' recent studies, that not only does HSV1 generate the main components of amyloid plaques and neurofibrillary tangles (NFTs) - beta-amyloid (A beta) and abnormally phosphorylated tau but also, by disrupting autophagy, it prevents degradation of these aberrant proteins, leading to their accumulation and deposition, and eventually to AD.

Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders.

Almost a hundred years ago, the main neuropathological features of Alzheimer's disease (AD) brain were discovered, yet the underlying cause(s) are still unknown, and the disease is basically untreatable. Despite the very numerous studies on the neuropathological features, the cause(s) of their production and whether they have an aetiological role in the disease or are merely end-products ("tombstones") are still unknown. Indeed, until fairly recently, the only known risk factors were age, Down's syndrome and head injury. A susceptibility factor, the type 4 allele of the apolipoprotein E gene was identified, but it is neither essential nor sufficient to cause AD, so other factors must be involved also. We investigated the possibility of a viral role and discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-epsilon4 it confers a high risk of AD. Subsequently, we found that APOE determines outcome of infection in several diseases caused by diverse infectious agents. Here we describe our studies, and the few others carried out elsewhere, on the mechanism of action of HSV1 and the dependence of the damage on APOE. We discuss, in relation to HSV1 action on lipids and to the spread of the virus via lipid rafts in brain, the possible involvement in AD of cholesterol, a vital and major component of the human brain, and the dispute over whether statins, drugs used for lowering cholesterol levels, are protective against the disease. We also link the damage due to two major consequences of HSV1 infection--inflammatory and oxidative processes--to lipid peroxidation in brain, and consider the influence of the different apoE isoforms in this process.

Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer's Disease.

Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer's disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia-are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia (SD), and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of SD is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop SD. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in AD, they greatly justify usage of antiherpes antivirals to treat AD. Three other studies are described which directly relate to HSV1 and AD: they deal respectively with lysosomal changes in HSV1-infected cell cultures, with evidence for a role of human herpes virus type 6 and 7 (HHV6 and HHV7) in AD, and viral effects on host gene expression, and with the antiviral characteristics of beta amyloid (Aß). Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia (FM), and with FM being associated with later development of SD. Studies on the link between epilepsy, AD and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-ε4, HHV6 and HSV1 in epilepsy.

Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link.

Three articles have very recently appeared that are of especial relevance to the causes of dementia and its potential treatment. The first two (Tsai et al., published in PLoS One in November 2017; Chen et al., published in the January/February 2018 issue of Journal of Clinical Psychiatry) demonstrate an increased risk of subsequent senile dementia (SD) development in patients with acute varicella zoster (herpes zoster) infection. These articles present data highly relevant to the third, and most important, paper-by Tzeng et al., published online in the journal Neurotherapeutics at the end of February 2018. These authors report that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.

Role of Microbes in the Development of Alzheimer's Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer's disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aß) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aß and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aß deposition via formation of non-toxic, soluble Aß/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aß. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the "amyloid cascade hypothesis," which so far has been quite unsuccessful, to a new "infection hypothesis," or perhaps more broadly, "innate immune system dysregulation hypothesis," which may well permit and lead to the discovery of new treatments for AD patients.