SARS-CoV-2 initiation and acceleration of AD pathology in the setting of endogenous and exogenous risk factors

Baylor College Of Medicine, Houston TX

Investigators

Abstract

The uncertain etiology of Alzheimer’s disease poses significant obstacles to the development of both therapeutic and prevention strategies. At the root of this quandary is the fact that familial disease accounts for a very small fraction of cases, with the vast majority remaining genetically sporadic. The most widely known risk factor, the ApoE4 allele of the gene coding for apolipoprotein E, has been identified, but mechanistic ties to disease development are still emerging. Neuroinflammation has long been suspected as a contributing factor, and regular exercise documented as a mitigating factor, with theories to explain their effects being posed, but again with little mechanistic proof. A picture of a very complex process of initiation and progression of Alzheimers disease and related dementias (AD/RD) including Pick’s disease, fronto-temporal dementia (FTD) and other tauopathies, is slowly emerging. A key factor in the etiology of AD/RD that repeatedly crops up is viral infection. COVID-19 has brought new attention to this factor, with the observation that a fraction of those infected experience “brain-fog”, a catch-all term that includes cognitive dysfunction, memory dysfunction and mental fatigue, marked by impaired ability to perform mental tasks compared to before the infection. Several factors however, complicate an understanding of the effect of COVID-19 on AD/RD and constitute the driving questions for this proposal: These include (1) What are the relative contributions of genetic risk factors and COVID-19 on initiation and progression of AD/RD? (2) What are the effects of SARS-CoV-2 variants: extinct strains e.g. Wuhan, alpha, delta vs. current strains e.g. omicron and its lineage, and their sequential infection on AD/RD initiation and progression? (3) What are the effects of prior infections with other highly prevalent viruses e.g. HSV-1 on the initiation and progression of AD/RD by SARS-CoV-2? Successful completion of this work will probe the relationship between COVID-19 and neurodegeneration, while yielding deep mechanistic insights into the role of SARS-CoV-2 in combination with HSV-1 in triggering/accelerating an AD phenotype and focus a search for therapeutic targets to counteract AD initiation/acceleration/progression.