The association of herpes zoster and influenza vaccinations with the risk of developing dementia: a population-based cohort study within the UK Clinical Practice Research Datalink.

BACKGROUND: Dementia affects ability to remember, think, or make decisions that interfere with doing everyday activities. There is no cure, therefore any prevention or delay of the onset is of importance. This study aims to investigate the association between zoster and influenza vaccinations and the risk of developing dementia. METHODS: We conducted a retrospective population-based cohort study using electronic health records from 1469 general practices contributing to the Clinical Practice Research Datalink (CPRD) Aurum database with linked hospital episode statistics (HES) and Office for National Statistics (ONS) mortality records. We built two 'matched cohorts': zoster vaccine (854,745 exposed individuals) matched with 8.8 million comparators without a history of zoster vaccination, and influenza vaccine (742,487 exposed individuals) matched with 7.12 million comparators without a history of vaccination as another comparator group. The cohorts were then followed to assess the association of exposure (vaccine) with outcome (dementia diagnosis). RESULTS: Zoster vaccination was associated with a lower risk of dementia diagnosis (adjusted hazard ratio (HR) 0.78 with 95% CI: 0.77-0.79), Alzheimer's diagnosis (adjusted HR 0.91 with 95% CI: 0.89-0.92 and other types of dementia (adjusted HR 0.71 with 95% CI: 0.69-0.72). Influenza vaccination also was associated with a slightly reduced hazard of dementia risk (adjusted HR 0.96 with 95% CI: 0.94-0.97). CONCLUSION: Both zoster vaccine for prevention of shingles / herpes zoster and influenza vaccine to prevent influenza were associated with diminished risk of dementia, with the zoster association appearing more pronounced.

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.

Establishment of a consensus protocol to explore the brain pathobiome in patients with mild cognitive impairment and Alzheimer's disease: Research outline and call for collaboration.

Microbial infections of the brain can lead to dementia, and for many decades microbial infections have been implicated in Alzheimer's disease (AD) pathology. However, a causal role for infection in AD remains contentious, and the lack of standardized detection methodologies has led to inconsistent detection/identification of microbes in AD brains. There is a need for a consensus methodology; the Alzheimer's Pathobiome Initiative aims to perform comparative molecular analyses of microbes in post mortem brains versus cerebrospinal fluid, blood, olfactory neuroepithelium, oral/nasopharyngeal tissue, bronchoalveolar, urinary, and gut/stool samples. Diverse extraction methodologies, polymerase chain reaction and sequencing techniques, and bioinformatic tools will be evaluated, in addition to direct microbial culture and metabolomic techniques. The goal is to provide a roadmap for detecting infectious agents in patients with mild cognitive impairment or AD. Positive findings would then prompt tailoring of antimicrobial treatments that might attenuate or remit mounting clinical deficits in a subset of patients.

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.

Shingles, Zostavax vaccination and risk of developing dementia: a nested case-control study-results from the UK Biobank cohort.

OBJECTIVES: To investigate the association between shingles and dementia, and between Zostavax vaccination and dementia. DESIGN: Nested case-control study. SETTINGS: Data were drawn from the UK Biobank cohort study with a total of 228 223 participants with Hospital Episodes Statistics and primary care linkage health records. PARTICIPANTS: The analyses included 2378 incident dementia cases and 225 845 controls. Inclusion criteria for incident cases were a dementia diagnosis 3 years or more after the first assessment date derived from all sources including International Classification of Diseases (ICD)-10, ICD-9, self-report and primary care linkage records. Subjects with no dementia code from all sources were coded as controls. Both shingles and Zostavax vaccination were investigated for their association with dementia risk. RESULTS: There was a small but non-significant increase in the risk of dementia in subjects with shingles diagnosed 3 years or more prior to dementia diagnosis (OR: 1.088 with 95% CI: 0.978 to 1.211). In those subjects who had had Zostavax vaccination, the risk of dementia significantly decreased (OR: 0.808 with 95% CI: 0.657 to 0.993). CONCLUSION: A history of shingles was not associated with an increased risk of dementia. In subjects who were eligible for the immunisation and vaccinated with Zostavax, we saw reduced risk of developing dementia.

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 Infections and Dementia: Rebutting Alternative Fact.

Recent commentary in Neurotherapeutics by Nath critically addresses the earlier report by Tzeng et al. that aggressive antiviral treatment (AVT) against herpes simplex virus (HSV) was associated with a later decrease in the incidence of Alzheimer's disease (AD). Nath raises issues that we respond to: we point out that (i) the treated group (probably with severe infection) is likely to harbor genetic risk alleles that predispose to both AD and HSV infection-the potential treatment bias cited by Nath would support (rather than challenge) the preventive effect of AVT; (ii) HSV is well known to establish persistent infection in the brain; and (iii) current AVT compounds used to combat herpes viruses are highly specific for this class of viruses. Instead of "alternative fact," the findings of Tzeng et al. argue in favor of clinical trials of AVT in AD.

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.