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.
The article by Wang et al. linking COVID-19 to Alzheimer’s disease (AD)  is of great interest, especially in view of the many lines of evidence linking herpes simplex virus type 1 (HSV1) to AD. Some of these are described below, together with the proposal that infection-induced reactivation of latent HSV1 in brain of elderly people is the pathway that links the two diseases.
Many studies reveal a number of features common to both AD and COVID-19. The type 4 allele of the gene for apolipoprotein E (APOE ɛ4) is a major susceptibility factor for AD and in COVID-19, it confers a risk of severe disease. SARS-CoV-2, like AD, causes inter alia neurocognitive impairment, olfactory dysfunction, excessive fatigue, and anxiety symptoms, and autopsies of COVID-19 patients’ brains and brains of experimentally infected animals have shown various types of neuropathological damage. The latter include severe acute effects on neuronal function and viability, and neuroinflammation, which impairs neurogenesis in the hippocampus . SARS-CoV-2 infects astrocytes and to a lesser extent neurons, and the viral genome has been detected in the brain of some sufferers [3, 4]. Intriguingly, it has been suggested that insults such as infections and pollution might reactivate not only latent viruses but also endogenous retroviruses which, on chronic activation, may eventually lead to cognitive impairment and dementia in genetically susceptible people 
There are many reports that COVID-19 leads to reactivation of HSV1 and of varicella zoster virus (VZV) (see, e.g., [6–11]). In the case of AD, several epidemiological studies have shown that infections in general increase risk of the disease [12–17], and there is some evidence also that certain types of vaccination might decrease AD/dementia risk [18–21].
As to experimental data implicating HSV1 infection and reactivation of HSV1 from latency in the subsequent development of AD, HSV1 infection of cultured neural-type cells was found to lead to accumulation of the main components of the characteristic features of AD brain, amyloid-β, and AD-like tau [22, 23]. HSV1 infection of brain models, 3D hiNSC cultures, causes occurrence of these and several other AD-like features  and in these models, VZV  and other infectious pathogens (Cairns, Itzhaki, and Kaplan, to be published) reactivate quiescent HSV1, with consequent expression of AD-like phenotypes. Further, in HSV1-infected mice, repeated reactivation of the virus by thermal stress leads to the production of AD-like features—formation of amyloid-β, AD-like tau, and neuroinflammation markers (astrogliosis, IL-1β, and IL-6), irreversible cognitive defects and eventually to occurrence of an AD-like phenotype .
The rationale for considering that HSV1 might be involved in AD was based firstly on the fact that in the rare but very serious acute disease that HSV1 causes in brain, herpes simplex encephalitis, the main regions most affected are those most affected also in AD . Secondly, HSV1 is a very common virus, infecting about 80% of the population by age 60: after infection, it remains in the body for life, known to reside in the peripheral nervous system (PNS) in latent form, where it is reactivated by events such stress, infections, and immunosuppression, causing direct viral damage and also inflammation. HSV1 reactivation in the PNS causes herpes labialis (cold sores), though in only some 25–40% of those infected; the other 60–75% are asymptomatic. (Asymptomatic infection occurs in other infectious diseases, including SARS-CoV-2, though many people seem unaware that “infect” does not necessarily mean “affect”). The prevalence and persistence of HSV1 meet the pre-requisites for a proposed cause of AD: high prevalence and late onset.
Investigation of the linkage between HSV1 and AD started in 1991 when HSV1 DNA was discovered (using PCR) in latent form in brain of a high proportion of elderly people, including AD patients . (In fact, HSV1 DNA had been detected previously in human brain, in immunosuppressed HSV1-seropositive patients, as revealed by in situ DNA hybridization; it was absent in brains of seronegative and/or non-immunosuppressed subjects, suggesting that immunosuppression caused reactivation of latent HSV1 in brain .) Later, it was discovered that HSV1 in brain of APOE ɛ4 carriers conferred a high risk of AD (and that APOE ɛ4 was a risk for herpes labialis, caused usually by HSV1 . More recently, many other studies using very diverse techniques have supported these observations, and the concept that HSV1 in brain of APOE ɛ4 carriers is a major cause of AD, resulting from repeated reactivation of the virus in brain (as in the PNS) leading to cumulative damage, including cognitive decline, and thence, to the development of AD.
Among the many supportive findings on HSV1’s link to AD, at least three population studies have found that HSV1 infection confers a risk of AD/dementia [31–33]. In contrast, there are several other studies that suggest that HSV1 does not confer a risk [34, 35]. However, the latter negative studies used less stringent criteria for HSV1-positivity and/or did not take into account APOE genotype, or that their “controls” almost certainly included a high proportion of infected but asymptomatic people; the latter would have diminished any difference in risk between “control” and infected groups.
A possible explanation suggested for the fact that infections in general increase the risk of AD was that infection-induced neuroinflammatory changes cause reactivation of latent HSV1 DNA present in brain . Consistent with this proposal are the AD-like features caused by HSV1 in 2D and 3D cell cultures, the reactivating effects of infection with VZV  and the thermal-induced recurrent reactivations in infected mice; all of these are attributable to upregulation of cytokines .
As to vaccinations and dementia, the apparent protective effect of various vaccines against AD/dementia (including BCG in the case of bladder cancer patients ), and the finding that BCG vaccination reduces the frequency and severity of cold sores , implying an inhibitory effect on HSV1 reactivation, might result from a vaccination-induced decrease in severity and/or frequency of infection and consequent decrease in HSV1 reactivation .
I therefore propose that SARS-CoV-2 and other events that cause brain damage can trigger reactivation of latent HSV1 in brain, that repeated reactivations—particularly in APOE ɛ4 carriers—lead eventually to AD, and that vaccinations, by reducing reactivations, might reduce the risk of AD.
Thus the study of Wang et al. , and the relevant findings on the neuropathological consequences of COVID-19, together with the fact that COVID-19 can reactivate herpesviruses, and that HSV1 reactivations lead to AD-like phenotypic changes, support a role for HSV1 reactivation as a major consequence of COVID, as well as a major cause of AD. Further relevant information might be provided by investigating whether the proportion of HSV1-seropositive APOE ɛ4 carriers was higher in those patients who progressed to AD than in those who did not progress to AD.
The author has no acknowledgments to report.
The author has no funding to report.
CONFLICT OF INTEREST
Ruth F. Itzhaki is an Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review.
Wang L , Davis PB , Volkow ND , Berger NA , Kaelber DC , Xu R ((2022) ) Association of COVID-19 with new-onset Alzheimer’s disease. J Alzheimers Dis 89: , 411–414.
Aghagoli G , Gallo Marin B , Katchur NJ , Chaves-Sell F , Asaad WF , Murphy SA ((2021) ) Neurological involvement in COVID-19 and potential mechanisms: A review. Neurocrit Care 34: , 1062–1071.
Radhakrishnan RK , Kandasamy M ((2022) ) SARS-CoV-2-mediated neuropathogenesis, deterioration of hippocampal neurogenesis and dementia. Am J Alzheimers Dis Other Demen 37: , 15333175221078418.
Crunfli F , Carregari VC , Veras FP , Silva LS , Nogueira MH , Antunes ASLM , ASLM, Vendramini PH , Valenca AGF , Brandão-Teles C , Zuccoli GDS , Reis-de-Oliveira G , Silva-Costa LC , Saia-Cereda VM , Smith BJ , Codo AC , de Souza GF , Muraro SP , Parise PL , Toledo-Teixeira DA , Santos de Castro ÍM , Melo BM , Almeida GM , Firmino EMS , Paiva IM , Silva BMS , Guimarães RM , Mendes ND , Ludwig RL , Ruiz GP , Knittel TL , Davanzo GG , Gerhardt JA , Rodrigues PB , Forato J , Amorim MR , Brunetti NS , Martini MC , Benatti MN , Batah SS , Siyuan L , João RB , Aventurato ÍK , Rabelo de Brito M , Mendes MJ , da Costa BA , Alvim MKM , da Silva Júnior JR , Damião LL , de Sousa IMP , da Rocha ED , Gonçalves SM , Lopes da Silva LH , Bettini V , Campos BM , Ludwig G , Tavares LA , Pontelli MC , Viana RMM , Martins RB , Vieira AS , Alves-Filho JC , Arruda E , Podolsky-Gondim GG , Santos MV , Neder L , Damasio A , Rehen S , Vinolo MAR , Munhoz CD , Louzada-Junior P , Oliveira RD , Cunha FQ , Nakaya HI , Mauad T , Duarte-Neto AN , Ferraz da Silva LF , Dolhnikoff M , Saldiva PHN , Farias AS , Cendes F , Moraes-Vieira PMM , Fabro AT , Sebollela A , Proença-Modena JL , Yasuda CL , Mori MA , Cunha TM , Martins-de-Souza D ((2022) ) Morphological, cellular, and molecularbasis of brain infection in COVID-19 patients. Proc Natl AcadSci U S A 119: , e2200960119.
Licastro F , Porcellini E ((2021) ) Activation of endogenous retrovirus, brain infections and environmental insults in neurodegeneration and Alzheimer’s disease. Int J Mol Sci 22: , 7263.
Le Balc’h P , Pinceaux K , Pronier C , Seguin P , Tadié JM , Reizine F ((2020) ) Herpes simplex virus and cytomegalovirus reactivationsamong severe COVID-19 patients. Crit Care 24: , 530.
Franceschini E , Cozzi-Lepri A , Santoro A , Bacca E , Lancellotti G , Menozzi M , Gennari W , Meschiari M , Bedini A , Orlando G , Puzzolante C , Digaetano M , Milic J , Codeluppi M , Pecorari M , Carli F , Cuomo G , Alfano G , Corradi L , Tonelli R , De Maria N , Busani S , Biagioni E , Coloretti I , Guaraldi G , Sarti M , Luppi M , Clini E , Girardis M , Gyssens IC , Mussini C ((2021) ) Herpes simplex virus re-activation inpatients with SARS-CoV-2 pneumonia: A prospective, observationalstudy. Microorganisms 9: , 1896.
Farid H , Khan M , Jamal S , Ghafoor R ((2022) ) Oral manifestations of Covid-19-A literature review. Rev Med Virol 32: , e2248.
Katz J , Yue S , Xue W ((2022) ) Herpes simplex and herpes zoster viruses in COVID-19 patients. Ir J Med Sci 191: , 1093–1097.
Chen J , Song J , Dai L , Post SR , Qin Z ((2022) ) SARS-CoV-2 infection and lytic reactivation of herpesviruses: A potential threat in the postpandemic era? J Med Virol 94: , 5103–5111.
Giacobbe DR , Di Bella S , Lovecchio A , Ball L , De Maria A , Vena A , Bruzzone B , Icardi G , Pelosi P , Luzzati R , Bassetti M ((2022) ) Herpessimplex virus 1 (HSV-1) reactivation in critically ill COVID-19 patients: A brief narrative review. Infect Dis Ther 11: , 1779–1791.
Sochocka M , Zwolinska K , Leszek J ((2017) ) The infectious etiology of Alzheimer’s disease. Curr Neuropharmacol 15: , 996–1009.
Ou YN , Zhu JX , Hou XH , Shen XN , Xu W , Dong Q , Tan L , Yu JT ((2020) ) Associations of infectious agents with Alzheimer’s disease: A systematic review and metaanalysis. J Alzheimers Dis 75: , 299–309.
Sipilä PN , Heikkilä N , Lindbohm JV , Hakulinen C , Vahtera J , Elovainio M , Suominen S , Väänänen A , Koskinen A , Nyberg ST , Pentti J , Strandberg TE , Kivimäki M ((2021) ) Hospital-treated infectious diseases and the risk of dementia: A large, multicohort, observational study with a replication cohort. Lancet Infect Dis 21: , 1557–1567.
Hernandez-Ruiz V , Letenneur L , Fülöp T , Helmer C , Roubaud-Baudron C , Avila-Funes JA , Amieva H ((2022) ) Infectious diseases and cognition: Do we have to worry? Neurol Sci 22: , 6215–6224.
Damiano RF , Guedes BF , de Rocca CC , de Padua Serafim A , Castro LHM , Munhoz CD , Nitrini R , Filho GB , Miguel EC , Lucchetti G , Forlenza O ((2022) ) Cognitive decline following acute viral infections: Literature review and projections for post-COVID-19. Eur Arch Psychiatry Clin Neurosci 272: , 139–154.
Sun J , Ludvigsson JF , Ingre C , Piehl F , Wirdefeldt K , Zagai U , Ye W , Fang F ((2022) ) Hospital-treated infections in early- and mid-life and risk of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis: A nationwide nested case-control study in Sweden. PLoS Med 19: , e1004092.
Verreault R , Laurin D , Lindsay J , De Serres G ((2001) ) Past exposure to vaccines and subsequent risk of Alzheimer’s disease. CMAJ 165: , 1495–1498.
Lophatananon A , Mekli K , Cant R , Burns A , Dobson C , Itzhaki R , Muir K ((2021) ) Shingles, Zostavax vaccination and risk of developing dementia: A nested case-control study-results from the UK Biobank cohort. BMJ Open 11: , e045871.
Veronese N , Demurtas J , Smith L , Michel JP , Barbagallo M , Bolzetta F , Noale M , Maggi S ((2022) ) Influenza vaccination reduces dementia risk: A systematic review and meta-analysis. Ageing Res Rev 73: , 101534.
Wu X , Yang H , He S , Xia T , Chen D , Zhou Y , Liu J , Liu M , Sun Z ((2022) ) Adult vaccination as a protective factor for dementia: A meta-analysis and systematic review of population-based observational studies. Front Immunol 13: , 872542.
Wozniak MA , Itzhaki RF , Shipley SJ , Dobson CB ((2007) ) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429: , 95–100.
Wozniak MA , Frost AL , Itzhaki RF ((2009) ) Alzheimer’s disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis 16: , 341–350.
Cairns DM , Rouleau N , Parker RN , Walsh KG , Gehrke L , Kaplan DL ((2020) ) A 3D human brain-like tissue model of herpes-induced Alzheimer’s disease. Sci Adv 6: , eaay8828.
Cairns DM , Itzhaki RF , Kaplan DL ((2022) ) Potential involvement of varicella zoster virus in Alzheimer’s disease via reactivation of quiescent herpes simplex virus type 1. J Alzheimers Dis 88: , 1189–1200.
De Chiara G , Piacentini R , Fabiani M , Mastrodonato A , Marcocci ME , Limongi D , Napoletani G , Protto V , Coluccio P , Celestino I , Li Puma DD , Grassi C , Palamara AT ((2019) ) Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog 15: , e1007617.
Ball MJ ((1982) ) Limbic predilection in Alzheimer dementia: Is reactivated herpesvirus involved? Can J Neurol Sci 9: , 303–306.
Jamieson GA , Maitland NJ , Wilcock GK , Craske J , Itzhaki RF ((1991) ) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33: , 224–227.
Saldanha J , Sutton RN , Gannicliffe A , Farragher B , Itzhaki RF ((1986) ) Detection of HSV1 DNA by in situ hybridisation in human brain after immunosuppression. J Neurol Neurosurg Psychiatry 49: , 613–619.
Itzhaki RF , Lin WR , Shang D , Wilcock GK , Faragher B , Jamieson GA ((1997) ) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349: , 241–244.
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 ((2018) ) Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections-a nationwide, population-based cohort study in Taiwan. Neurotherapeutics 15: , 417–429.
Shim Y , Park M , Kim J ((2022) ) Increased incidence of dementia following herpesvirus infection in the Korean population. Medicine (Baltimore) 101: , e31116.
Lopatko Lindman K , Hemmingsson ES , Weidung B , Brännström J , Josefsson M , Olsson J , Elgh F , Nordström P , Lövheim H ((2021) ) Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Alzheimers Dement (N Y) 7: , e12119.
Schnier C , Janbek J , Williams L , Wilkinson T , Laursen TM , Waldemar G , Richter H , Kostev K , Lathe R , Haas GJ ((2021) ) Antiherpetic medication and incident dementia: Observational cohort studies in four countries. Eur J Neurol 28: , 1840–1848.
Murphy MJ , Fani L , Ikram MK , Ghanbari M , Ikram MA ((2021) ) Herpes simplex virus 1 and the risk of dementia: A population-based study. Sci Rep 11: , 8691.
Itzhaki RF , Dobson CB ((2002) ) Alzheimer’s disease and herpes. CMAJ 167: , 13.
Pittet LF , Curtis N ((2021) ) Does bacillus Calmette-Guerin vaccine prevent herpes simplex virus recurrences? A systematic review. Rev Med Virol 31: , 1–9.
Klein BY , Greenblatt CL , Gofrit ON , Bercovier H ((2022) ) BacillusCalmette-Guérin in immuno-regulation of Alzheimer’s disease. Front Aging Neurosci 14: , 861956.