Pandey JP, Olsson J, Weidung B, Kothera RT, Johansson A, Eriksson S, Hallmans G, Elgh F, Lövheim H. An Ig γ Marker Genotype Is a Strong Risk Factor for Alzheimer Disease, Independent of Apolipoprotein E ε4 Genotype. J Immunol. 2020 Sep 1;205(5):1318-1322. Epub 2020 Jul 24 PubMed.

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  1. In this study, Pandey et al. report that a γ marker (GM) allotype more susceptible to HSV-1 immune evasion mechanisms is present at higher rates in subjects with Alzheimer’s disease. The authors show that carriers homozygous for the GM 17 allotype were significantly more present among AD cases than controls. The fourfold increased risk of AD in these carriers was independent of APOE risk.

    These are very interesting results, at the levels of both AD genetics and the potential infectious etiology of AD. The IGHV locus has been previously implicated to be associated with AD by GWAS, adding to the strength of the study. It is also worth noting that other viral-infection-related genes have been previously associated with AD, including PILRA and ITGB3

    GM 17’s significantly increased affinity for HSV1’s gE-gI complex, presenting a more effective immune modulation by the virus, is an intriguing mechanism for a potential viral etiology of AD, but not unique to HSV-1. Human cytomegalovirus glycoprotein 34 and Staphylococcus aureus protein A both promote immune suppression during infection and bind to the same Fcγ, suggesting that other pathogens should also be explored for their potential roles in AD etiology.

    So far, we do not have a smoking gun for a potential viral etiology of AD. But many of us are actively exploring it. Pandey et al. presents a case for the role of HSV-1 in AD and starts to address the recurring criticism that the penetrance of HSV-1 infection in the population does not correlate with the incidence of AD pathology.

    View all comments by William Eimer

  2. The coronavirus pandemic has placed in stark relief our primitive understanding of virology and the complications caused by viral infection because of immunological, immunogenetic, inflammatory, coagulopathic, and vasculopathic events. This an especially apt time for the neurodegenerative disease field to revisit the longstanding but still controversial implication that herpesviruses may sometimes play some roles in the pathogenesis of AD. A recent "big data" paper by a multi-lab collaborative group (Readhead et al., 2018) reignited the focus on herpes viruses in AD. 

    A related area of investigation was highlighted in this Alzforum story. Pandey and colleagues focus on evidence that allotypes of immune-inflammatory system components may play roles in AD risk. The GM17 allotype of IgG1, linked in this paper to AD, has a history of specifying host response to a variety of viral infections.

    Another entirely different virus-neurodegeneration story was recently reported (Dembny et al., 2020). These investigators demonstrated that retroviral proteinase HERVK RNA can apparently cause neurodegeneration through activation of Toll-like receptors. This mechanism is invoked as a potential explanation for reports that HERVK plays a role in ALS (Li et al., 2015). The notion that an RNA can be neuroactive dovetails well with other evidence that RNAs and microRNAs can play either pathogenic or protective roles in the pathogenesis of a range of neurodegenerative diseases (e.g., miR155 in Readhead et al., 2020). 

    A key question is whether the new data implicating viruses might be actionable. To investigate that possibility, Gold et al. (2019) conducted a clinical trial in ALS using a cocktail of multiple antiviral drugs. That trial generated sufficiently convincing clinical and biomarker evidence for safety and benefit that a large international trial of the same cocktail is now being planned. Devanand et al. (2020) have set out along a similar path in their trial of valacyclovir in AD.

    Obviously, the current acute public health emergency calls for advancing our understanding of viruses and the pleiotropic havoc they can wreak, both acutely and chronically. One hopes that the intense current interest in virology and immunology will generate new information and tools that will enable us to clarify not only the multi-organ pathogenesis of SARS-CoV2 disease, but also the neuropathogenesis that potentially links herpesviruses to  AD.

    References:

    Dembny P, Newman AG, Singh M, Hinz M, Szczepek M, Krüger C, Adalbert R, Dzaye O, Trimbuch T, Wallach T, Kleinau G, Derkow K, Richard BC, Schipke C, Scheidereit C, Stachelscheid H, Golenbock D, Peters O, Coleman M, Heppner FL, Scheerer P, Tarabykin V, Ruprecht K, Izsvák Z, Mayer J, Lehnardt S. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight. 2020 Apr 9;5(7) PubMed.

    Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, Mintz A, Wisniewski T, Acosta E, Pollina J, Katsikoumbas M, Bell KL, Pelton GH, Deliyannides D, Prasad KM, Huey ED. Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open. 2020 Feb 6;10(2):e032112. PubMed.

    Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, van Eijk RP, Nath A, Garcia Montojo M, Norato G, Santamaria UA, Rogers ML, Malaspina A, Lombardi V, Mehta PR, Westeneng HJ, van den Berg LH, Al-Chalabi A. Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener. 2019 Nov;20(7-8):595-604. Epub 2019 Jul 8 PubMed.

    Li W, Lee MH, Henderson L, Tyagi R, Bachani M, Steiner J, Campanac E, Hoffman DA, von Geldern G, Johnson K, Maric D, Morris HD, Lentz M, Pak K, Mammen A, Ostrow L, Rothstein J, Nath A. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015 Sep 30;7(307):307ra153. PubMed.

    Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, Reiman EM, Schadt EE, Ehrlich ME, Gandy S, Dudley JT. Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron. 2018 Jul 11;99(1):64-82.e7. Epub 2018 Jun 21 PubMed.

    Readhead B, Haure-Mirande JV, Mastroeni D, Audrain M, Fanutza T, Kim SH, Blitzer RD, Gandy S, Dudley JT, Ehrlich ME. miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease. Acta Neuropathol. 2020 Sep;140(3):295-315. Epub 2020 Jul 14 PubMed.

    View all comments by Sam Gandy

  3. It's heartwarming to see increased openness to the relatively unexplored possibilities that microbes can trigger Alzheimer's. I hope in this rush to pinpoint intracellular and genomic influence, we will still urge epidemiologists to further investigate possible macro clues, such as reports that neurosurgeons and caregivers of Alzheimer's patients develop more Alzheimer's disease than statistics might predict.

    View all comments by Leslie Norins

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