Summary The COVID-19 pandemic constitutes a significant challenge to health care systems in the United States and abroad. A systemic compromise of the organism following SARS-CoV-2 infection has emerged as an important factor associated with COVID-19 severity, disproportionally affecting older patients with comorbidities such as hypertension, diabetes, and dementia. In addition to respiratory symptoms, COVID-19 patients can present neurological symptoms, ranging from the frequent loss of smell to rare but severe neurovascular and neuroinflammatory events. These neurological symptoms disproportionally affect patients with Alzheimer’s disease (AD) and can potentially lead to clinical scenarios previously associated with faster neurodegenerative progression and worse behavioral outcomes. The involvement of the brain during COVID-19 and the mechanisms of interaction between SARS-CoV-2 and AD pathological routes, however, remain poorly understood. Our long-term goal in this project is to further our knowledge on how neuropathology may contribute to the complex clinical presentation of COVID-19 and how SARS-CoV-2 infection and AD can negatively synergize in vulnerable patients. The objective of this grant is to characterize the short-term effects of SARS- CoV-2 in the brain during the acute stage of the infection in both young and aged diabetic animals, and a possible protective effect of immunotherapeutic prophylaxis. The central hypothesis is that SARS-CoV-2 is both neuroinvasive and neurotropic, accessing the brain and infecting neurons and potentially other cells within the CNS, leading to neurodegeneration, inflammation, and a brain environment conducive to dementia. The rationale is that other human coronaviruses are neuroinvasive and neurotropic, including the closely related SARS-CoV- 1, causing direct damage to neurons and myelin and triggering neuroinflammatory processes. Furthermore, the SARS-CoV-2 entry receptor ACE2 has been previously implicated in AD, and other coronavirus infections have been reported to trigger adaptive intracellular cascades linked to neurodegeneration. Our specific aims will test the following hypotheses: (Aim 1) SARS-CoV-2 is neuroinvasive, neurotropic, and its infection of brain cells causes neuronal and myelinic damage; (Aim 2) SARS-CoV-2 infection triggers neuroinflammation and cytokine release, and prophylactic treatment with immunotherapeutic agents, such as convalescent plasma and monoclonal antibodies, can affect the brain response; (Aim 3) COVID-19 and AD neuropathological routes interact directly at the molecular level through the regulation of ACE2 and stress response pathways. This contribution is significant as it will considerably advance our knowledge of COVID-19 pathology, opening new avenues of treatment and care for a major public health concern, while also providing the necessary framework to understand the long-term consequences of COVID-19 and its impact on AD pathology. The proposed research is ...