Lopatko Lindman K, Hemmingsson ES, Weidung B, Brännström J, Josefsson M, Olsson J, Elgh F, Nordström P, Lövheim H. Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y). 2021;7(1):e12119. Epub 2021 Feb 14 PubMed.

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  1. This is a very well-done study and one of the largest showing that not only herpes simplex (HSV), but also herpes zoster (VZV), increases the risk of dementia, and that treatment lowers that risk significantly.

    This and other European studies are consistent in showing a moderate effect of herpes/antivirals, in contrast to the large effect demonstrated in a Taiwanese sample. Overall, this study supports the idea that herpes infections are contributing to Alzheimer's disease, either directly or by worsening cognitive function, and thereby increasing the likelihood of a diagnosis of dementia. The fact that antiviral drugs reduce the risk significantly points to a potential etiologic basis for the observed effect.

    Some questions remain about the dose and duration of antiviral drug treatment. Most clinical treatment of herpes infections is of short duration for acute episodes, with prolonged doses of antiviral drugs only reserved for recurrent infections. However, these epidemiological/large database studies are unable to identify dose and duration accurately. This is a clinically important limitation because the question is not only whether antiviral drugs work to prevent or treat Alzheimer’s disease, but if they do, what dose to use and for how long. These questions remain to be answered in clinical trials.

    View all comments by Davangere Devanand

  2. The study by Karin Lopatko Lindman et al. is an excellent observational cohort study that supports the idea of a potential weak association between herpes diagnosis, antiherpetic treatment, and subsequent incident dementia. People exposed to routine treatment for herpes infections (94 percent one-off exposures to Acyclovir and Valacyclovir) had approximately 11 percent lower risk of incident dementia compared to those not exposed to antiherpetics. This does not sound like a substantial decrease, but given the large number of people exposed to antiherpetic treatments and the large number of people at risk of developing dementia, it's quite a difference.

    Lopatko Lindman et al. also found that people diagnosed with herpes infection but not treated with antiherpetics had a 50 percent increased risk of incident dementia compared to those never diagnosed and never treated. The authors then compared people diagnosed/treated with those diagnosed/untreated and report a 25 percent reduced risk of subsequent dementia in the treated.

    But who are the people who are getting diagnosed but not treated? In the study, people with a registered herpes diagnosis were diagnosed in the secondary-care setting only (inpatient and outpatient); so these would presumably be those with severe clinical symptoms and from sexual health clinics, ophthalmology, dermatologists, and other specialist clinics. Why are they not treated? In the U.K. and in Denmark, hospital-administered drugs would usually not be included in a prescription database (unless the drugs are prescribed during the hospital visit and subsequently redeemed from a pharmacy)—is that a reason? It is unclear from the study whether the diagnosed/treated group had received the treatment after diagnosis date, or if some people in that group were considered diagnosed/treated regardless of when the information on treatment was recorded in relation to the secondary care diagnosis. The index date in the study was either the treatment or diagnosis date, and the different start points for the analyzed groups (from treatment date for the diagnosed/treated group versus from diagnosis date for the diagnosed/untreated) might have allowed for a longer follow-up period in the treated group since it is likely that the date of treatment preceeded the date of diagnosis. In short, the findings highlight the need to consider whether hospital-diagnosed herpes infections show different associations, and whether patient-characteristics of those diagnosed in the primary versus secondary-care settings could shed light on the observed associations and the link between herpes virus infection and subsequent dementia.

    In view of the discussion about validity of ICD codes to subclassify dementia, we understand the authors’ reluctance to subclassify dementia (dementia can’t be subclassified by the medication alone). However, a comparison of associations of medication/herpes infection with Alzheimer’s dementia with associations of medication/herpes infection with vascular dementia would allow some differentiation of true effects from residual confounding.

    Does herpes cause dementia and is antiherpetic medication protecting people from getting dementia? Like us, Lopatko Lindman et al. wisely stay well clear of an answer. Too many unmeasured factors affect the process. Using routinely collected health data, we can't determine if people not exposed to antiherpetics are ”the same” (in regard to future dementia risks) as people exposed to antiherpetics. However, researchers have now collected a large body of evidence that the large association reported by Tzeng et al. was probably more of an exception to the rule and that routine antiherpetic treatment (at least in Northern Europe) will not substantially reduce the burden of dementia (Tzeng et al., 2018). 

    References:

    Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC. Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics. 2018 Apr;15(2):417-429. PubMed.

    View all comments by Janet Janbek

  3. In this interesting new study, Lopatko Lindman et al. examined the impact of antiviral treatment on long-term risk of dementia in a large Swedish registry-based cohort, focusing on herpes simplex virus (HSV) and varicella zoster virus (VZV), two highly penetrant viruses in the population.

    In those with diagnoses of VSV or HS, the authors observed increased risk of dementia associated with untreated positive herpes diagnoses, and decreased risk with antiviral treatments. These results align very well with previous cohort studies from Taiwan and South Korea that reported reduced risk for Alzheimer’s disease (AD) associated with antiviral treatment of those with herpes infections versus those who were untreated. Importantly, this does not mean that treating with antivirals broadly decreases risk for AD. In this and previous studies, the implication is that leaving a viral infection untreated places one at higher risk for AD versus treating the infection with an antiviral.

    Interestingly, the authors noted a greater degree of risk for AD stemming from VZV versus HSV. As such, their study implies that one’s personal history regarding exposure to specific viral infections may become increasingly important in assessing an individual’s future risk for dementia. A potential role for viruses (and other pathogens) in AD remains a very controversial topic, with multiple conflicting papers being published just over the past year, alone. As pointed out by the authors, these discrepancies could be rooted in both variability of the pathogens (both HSV and VZV elicit risk) and factors impacting the immune response, e.g. APOE genotype, or number of reinfections.

    Our own proof-of-concept studies in AD models demonstrating the role of the Aβ protein as an antimicrobial peptide shows that Aβ can be nucleated by a variety of pathogens, from viruses to bacteria to fungi, as part of innate immune host defense in the brain. However, it must be emphasized that without a smoking gun showing overabundance of a particular virus (or other pathogen) in the brains of AD patients, we must mainly rely on data such as that provided in cohort studies, such as this new one from the Lövheim group, to obtain an idea of the types of microbial pathogens that may play role in the etiology of AD.

    View all comments by Rudy Tanzi

  4. This is an interesting and useful study for at least two reasons: Firstly, it adds to the four previous studies on risk of subsequent dementia for those treated with antivirals, specifically antiherpetics, and secondly, the data, along with the previous studies, suggest that varicella zoster herpes virus (VZV) as well as herpes simplex virus 1 (HSV1) is involved in dementia. Proving definitively that antiviral treatment before any signs of dementia appear protects against dementia would clearly be of great potential importance, as prevention of a disease is obviously greatly preferable to treatment. It would obviate the intense and protracted suffering of patients and their families, and it would also avert the great economic costs of the disease.

    This paper supports the four previous positive findings (Tsai et al., 2017; Chen et al., 2018; Bae et al., 2020; Schnier et al., 2021) that VZV, like HSV1, confers a risk of dementia, supported further by epidemiological and serological research by myself and colleagues (Lophatananon et al., submitted; Mekli et al., submitted). However, in respect to antiviral effects, the current study agrees with three of the previous studies that found a protective association, but disagrees with Schnier et al., who found none. The likely explanation for the latter—treatment with only a single dose of antiviral—has been pointed out in previous postings (see Jan 2021 news). 

    The actual sequence of events affording this protection is unknown. As I and Richard Lathe pointed out, the protective effect is extremely puzzling, because durations of treatment were days and weeks rather than months or years, and after each treatment the antiviral would have remained in the body for only a few days, and much would have been excreted (Itzhaki and Lathe, 2018). We suggested one possible explanation, based on research by my group some 25 years ago that the virus, which resides in the peripheral nervous system of most adults, might travel from the PNS to the central nervous system in older age as the immune system declines (Itzhaki et al., 1997). Assuming that this is correct, we speculated that antiviral treatment might prevent the transit of HSV1 into the brain, or possibly delay its transit. Alternatively, in older people, if the virus has already reached the brain, the antiviral might reduce the frequency of reactivation—as intimated by Lopatko Lindman et al. However, an argument against both suggestions would be that even longer durations of treatment or more frequently given doses, as reported in the current study, would presumably have been countered by subsequent passage of the virus to the CNS, or resumption of its usual reactivations in the CNS in those for whom antiviral treatment made no impact on dementia risk.

    As to whether or not VZV action is direct, i.e., resulting from its being present in brain and its subsequent reactivation there, or whether instead it is indirect, acting via inflammatory processes which cause reactivation of HSV1 resident in brain is also uncertain. Such indirect, inflammation-induced reactivation of HSV1 in the CNS could presumably be caused also by infective agents other than VZV in the PNS (Wozniak and Itzhaki, 2010). Lopatko Lindman et al. skate rather delicately around this issue, stating that the presence of VZV-DNA in postmortem brain tissue specimens have not yet been unambiguously established. In fact, my lab sought VZV DNA in brain (Lin et al, 1997) but did not detect it, whereas Hemling et al. did find it, though they did not find HSV1 DNA (Helming et al., 2003). Surprisingly, their detection of the DNA of both viruses was far less sensitive than was ours. Involvement of VZV in dementia has been suggested by other approaches, such as the study by Grahn and colleagues, who showed that after acute VZV infection, patients who had suffered predominantly CNS manifestations showed significant cognitive decline three years later (Grahn et al., 2013). 

    It would be of great interest to discover whether or not VZV does reside in the brain and to discover whether HSV1 is the sole neurotropic virus (or bacterium) resident there. Other more minor points of interest which need to be elucidated, though they are often not specified in such databases, is whether HSV means HSV1—or, far less likely, HSV2—genital herpes, the role of APOE genotypes, and details of the type, duration, etc., of the antiviral used. 

    References:

    Tsai MC, Cheng WL, Sheu JJ, Huang CC, Shia BC, Kao LT, Lin HC. Increased risk of dementia following herpes zoster ophthalmicus. PLoS One. 2017;12(11):e0188490. Epub 2017 Nov 22 PubMed.

    Chen VC, Wu SI, Huang KY, Yang YH, Kuo TY, Liang HY, Huang KL, Gossop M. Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study. J Clin Psychiatry. 2018 Jan/Feb;79(1) PubMed.

    Bae S, Yun SC, Kim MC, Yoon W, Lim JS, Lee SO, Choi SH, Kim YS, Woo JH, Kim SY, Kim SH. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2020 Jul 1; PubMed.

    Schnier C, Janbek J, Williams L, Wilkinson T, Laursen TM, Waldemar G, Richter H, Kostev K, Lathe R, G Haas J. Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol. 2021 Jun;28(6):1840-1848. Epub 2021 Mar 19 PubMed.

    Itzhaki RF, Lathe R. Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link. J Alzheimers Dis. 2018;64(2):363-366. PubMed.

    Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.

    Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer's disease: hope for the future?. Ther Adv Neurol Disord. 2010 May;3(3):141-52. PubMed.

    Lin WR, Casas I, Wilcock GK, Itzhaki RF. Neurotropic viruses and Alzheimer's disease: a search for varicella zoster virus DNA by the polymerase chain reaction. J Neurol Neurosurg Psychiatry. 1997 Jun;62(6):586-9. PubMed.

    Hemling N, Röyttä M, Rinne J, Pöllänen P, Broberg E, Tapio V, Vahlberg T, Hukkanen V. Herpesviruses in brains in Alzheimer's and Parkinson's diseases. Ann Neurol. 2003 Aug;54(2):267-71. PubMed.

    Grahn A, Nilsson S, Nordlund A, Lindén T, Studahl M. Cognitive impairment 3 years after neurological Varicella-zoster virus infection: a long-term case control study. J Neurol. 2013 Nov;260(11):2761-9. Epub 2013 Jul 31 PubMed.

    View all comments by Ruth Itzhaki

  5. This paper deals with an interesting aspect of the possible role of herpesvirus infection in dementia. The authors recognized that antiviral treatment might be associated with a reduced long-term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesvirus infections are involved in the pathogenesis of Alzheimer's disease.

    A point that might increase the significance of these results is also the classification of the patients by their genetic background. We have previously demonstrated that a gene, KIR2DL2, that is expressed as a receptor on the surface of Natural killer cells, modifies the susceptibility to herpesvirus infection and might have a role also in the response to antiviral therapies (Rizzo 2020). The subdivision of the population on the basis of this gene, which can be present or absent in the individual genome, might increase the accuracy of the results obtained. 

    References:

    Rizzo R. Controversial role of herpesviruses in Alzheimer's disease. PLoS Pathog. 2020 Jun;16(6):e1008575. Epub 2020 Jun 18 PubMed.

    View all comments by Roberta Rizzo

  6. In the span of fewer than two months after the report of Schnier and colleagues finding little to no solid evidence between herpes infection and the incidence of dementia in four European health records (Schnier et al., 2021), Lopatko Lindman and colleagues refuel the debate on the viral hypothesis of Alzheimer’s disease (AD).

    The authors show a clear positive association between herpes infections and dementia conversion by analyzing two very large, nationwide Swedish health records. This report is in alignment with the Taiwanese studies (Bae et al., 2020; Chen et al., 2018; Tzeng et al., 2018) and previous work from the same group demonstrating that seropositivity to herpes simplex virus is associated with an increased risk of late-onset AD (Lövheim et al., 2014, 2019). Adding to the existing literature, the current paper analyzes a very large, longitudinal dataset with follow-up visits over a 12-year time span, allowing assessment of the effect of recurrent infections, which are typical for herpesviridae.

    Indeed, the authors show that from the first infection, the risk of AD increases over time. The dataset is controlled for confounding factors such as co-symptomatic conditions, pharmacological treatments, and education. Herpes simplex-1 or -2 (generally termed HSV) and herpes zoster virus (VZV) diagnoses were based on clinical reports and not on molecular validation, which in most retrospective studies is missing anyway.

    Interestingly, higher morbidity of VZV (1.6 hazard ratio) as compared to HSV (1.4 HR) was found, which can be explained by the topology of VZV, with a higher risk of CNS penetrance than HSV. Furthermore, these results aligned with previous studies analyzing the incidence of herpes ophtalmicus in dementia (Tsai et al., 2017; Chen et al., 2018) and even the work of Schnier showing an increased hazard ratio of 1.2 for herpes zoster in the Disease Analyzer dataset (Schnier et al., 2021). From Lopatko Lindman’s report, confirming the higher degree of severity caused by VZV infections, the majority of the cases in the Swedish datasets are treated VSV (81.3 percent) as compared to treated HSV (22 percent). Based on the fact that all antivirals (ATV) are effective in treating both types of herpesviridae infection, it is likely that the protective effects observed in the group with ATV treatment (HR: 0.89) are more attributed to curbing infections of VZV rather than HSV.

    In alignment with a weighted prevalence of VZV infections in the dataset, the paper also shows a reduction in the number of stroke cases from 4.2 percent  to 2.6 percent, which strongly evokes the reported association of VZV with vascular disease (Lian et al., 2017). There is increasing evidence for a vascular component in AD, particularly in chronic low-grade inflammation (Bathini et al., 2020), which might be due to viral neurotoxicity and which may explain the synergistic effect of ApoE4  in increasing the risk for AD in subjects suffering from herpes infections (Lövheim et al., 2019; Itzhaki and Wozniak, 2006).  Vascular neuropathology, neuroinflammation, and neurodegeneration are intimately intertwined in the multifactorial etiology of AD. Additional well-controlled clinical studies, but also preclinical research with clinically relevant models and appropriate vectors, could revamp the vector hypothesis of AD (Itzhaki et al., 1997) and offer alternative therapeutic/preventive strategies.

    References:

    Bae S, Yun SC, Kim MC, Yoon W, Lim JS, Lee SO, Choi SH, Kim YS, Woo JH, Kim SY, Kim SH. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: a population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2020 Jul 1; PubMed.

    Bathini P, Dupanloup I, Zenaro E, Terrabuio E, Fischer A, Ballabani E, Doucey MA, Alberi L. Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology. Research Square, Aug 18, 2020. Research Square.

    Chen VC, Wu SI, Huang KY, Yang YH, Kuo TY, Liang HY, Huang KL, Gossop M. Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study. J Clin Psychiatry. 2018 Jan/Feb;79(1) PubMed.

    Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.

    Itzhaki RF, Wozniak MA. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders. Prog Lipid Res. 2006 Jan;45(1):73-90. PubMed.

    Lian Y, Zhu Y, Tang F, Yang B, Duan R. Herpes zoster and the risk of ischemic and hemorrhagic stroke: A systematic review and meta-analysis. PLoS One. 2017;12(2):e0171182. Epub 2017 Feb 8 PubMed.

    Lövheim H, Gilthorpe J, Johansson A, Eriksson S, Hallmans G, Elgh F. Herpes simplex infection and the risk of Alzheimer's disease-A nested case-control study. Alzheimers Dement. 2014 Oct 7; PubMed.

    Lövheim H, Norman T, Weidung B, Olsson J, Josefsson M, Adolfsson R, Nyberg L, Elgh F. Herpes Simplex Virus, APOEɛ4, and Cognitive Decline in Old Age: Results from the Betula Cohort Study. J Alzheimers Dis. 2019;67(1):211-220. PubMed.

    Schnier C, Janbek J, Williams L, Wilkinson T, Laursen TM, Waldemar G, Richter H, Kostev K, Lathe R, G Haas J. Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol. 2021 Jun;28(6):1840-1848. Epub 2021 Mar 19 PubMed.

    Tsai MC, Cheng WL, Sheu JJ, Huang CC, Shia BC, Kao LT, Lin HC. Increased risk of dementia following herpes zoster ophthalmicus. PLoS One. 2017;12(11):e0188490. Epub 2017 Nov 22 PubMed.

    Tzeng NS, Chung CH, Lin FH, Chiang CP, Yeh CB, Huang SY, Lu RB, Chang HA, Kao YC, Yeh HW, Chiang WS, Chou YC, Tsao CH, Wu YF, Chien WC. Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections-a Nationwide, Population-Based Cohort Study in Taiwan. Neurotherapeutics. 2018 Apr;15(2):417-429. PubMed.

    View all comments by Lavinia Alberi

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  1. Herpes Update—Virus Increases Dementia Risk in Sweden