SARS-CoV-2 initiation and acceleration of AD pathology in the setting of endogenous and exogenous risk factors - The uncertain e,ology of Alzheimer’s disease poses significant obstacles to the development of both therapeu,c and preven,on strategies. At the root of this quandary is the fact that familial disease accounts for a very small frac,on of cases, with the vast majority remaining gene,cally sporadic. The most widely known risk factor, the ApoE4 allele of the gene coding for apolipoprotein E, has been iden,fied, but mechanis,c ,es to disease development are s,ll emerging. Neuroinflamma,on has long been suspected as a contribu,ng factor, and regular exercise documented as a mi,ga,ng factor, with theories to explain their effects being posed, but again with liGle mechanis,c proof. A picture of a very complex process of ini,a,on and progression of Alzheimers disease and related demen,as (AD/RD) including Pick’s disease, fronto-temporal demen,a (FTD) and other tauopathies, is slowly emerging. A key factor in the e,ology of AD/RD that repeatedly crops up is viral infec,on. COVID-19 has brought new aGen,on to this factor, with the observa,on that a frac,on of those infected experience “brain-fog”, a catch-all term that includes cogni,ve dysfunc,on, memory dysfunc,on and mental fa,gue, marked by impaired ability to perform mental tasks compared to before the infec,on. Several factors however, complicate an understanding of the effect of COVID-19 on AD/RD and cons%tute the driving ques%ons for this proposal: These include (1) What are the rela,ve contribu,ons of gene,c risk factors and COVID-19 on ini,a,on and progression of AD/RD? (2) What are the effects of SARS-CoV-2 variants: ex,nct strains e.g. Wuhan, alpha, delta vs. current strains e.g. omicron and its lineage, and their sequen,al infec,on on AD/RD ini,a,on and progression? (3) What are the effects of prior infec,ons with other highly prevalent viruses e.g. HSV-1 on the ini,a,on and progression of AD/RD by SARS-CoV-2? Successful comple,on of this work will probe the rela,onship between COVID-19 and neurodegenera,on, while yielding deep mechanis,c insights into the role of SARS-CoV-2 in combina,on with HSV-1 in triggering/accelera,ng an AD phenotype and focus a search for therapeu,c targets to counteract AD ini,a,on/accelera,on/progression.
