A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimer's disease

Abstract The parent grant for this supplement application is R01 AG067193, "A geroscience approach for treating Alzheimer's disease". The supplement proposal is an extension of the parent grant and is titled "A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimers disease". The extension is designed to look at the complications of COVID-19 in the presence of cognitive impairment and neuropathological lesions of Alzheimer's disease in an aging mouse model. This is translationally relevant because patients with cognitive impairment related to Alzheimer's disease (AD) are at increased risk for complications of SARS-CoV-2 infection. Several factors are involved including cognitive impairment resulting in failure to follow exposure guidelines, such as crowd mingling, hand washing and other decontamination procedures. In addition, many individuals that require various levels of intensive care may come in close contact with others with similar poor health conditions that may be carrying the virus. Lastly, the debilitating effects of AD may inherently increase susceptibility to the severe complications of SARS-CoV-2 infection known to occur in older frail people. For these reasons, it is critical to investigate the mitigating factors associated with increasing resilience to pathological consequences of infection to prevent increased morbidity and mortality in an already susceptible elderly population. Given that a major risk factor for developing severe and fatal SARS-CoV-2 pathology is aging, it is thus a centerpiece for the geroscience concept that examines the relationship between biological aging and age-related diseases through multiple processes, and that aging intervention requires targeting multiple aging processes. Our parent grant is set up to address this concept for AD. The development of a multidrug cocktail that targets multiple aging processes and increases resilience to AD pathology should, by definition, also increase resilience to SARS-CoV-2 pathology in AD patients. The hypothesis of this supplement proposal is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, targeting multiple aging processes, will increase resilience to the pathological consequences of SARS-CoV-2 infection in an aging mouse model of AD. Aim 1 will investigate effects of treatment with an anti-aging drug cocktail in AD mice infected with SARS-CoV-2. Aim 2 will develop pathology profiles to show that treatment of AD mice with an anti-aging drug cocktail will enhance resilience and improve health by targeting processes of aging and prevent the devastating pathology caused by SARS-CoV-2 infection. This approach has tremendous clinical health implications for AD patients but perhaps just as important for individuals in the early stage of disease such as mild cognitive impairment. The concept of a drug cocktail that could successfully increase resilience to COVID-19 pathology in Alzheimers disease patients would be expected to have a significant impact on the health of people at increased risk for infection.