PROJECT SUMMARY COVID-19 is associated with cognitive impairment that may persist long after infection. COVID-19 risk factors overlap with those for Alzheimer’s disease (AD), including older age, the APOE4 allele, and vascular dysfunction, suggesting that pathology from one condition may exacerbate pathogenesis of the other. Blood- brain barrier (BBB) dysfunction may serve as a common pathogenic mechanism, as BBB breakdown has been identified in individuals at risk for AD and may facilitate COVID-19-related neural injury via binding of SARS- CoV-2 to cerebrovascular endothelial cells or via virally-mediated neuroinflammation. Sex is also a risk factor for both diseases, with increased AD risk for women and sex-specific risk for acute and chronic COVID-19 symptoms, which may be partially mediated by sex hormone regulation of SARS-CoV-2 binding, inflammation, immune activity, or BBB dysfunction. The intersection of latent AD neuropathology with neuroinflammation or cerebrovascular dysfunction triggered by COVID-19 among the aging population may ignite a perfect storm of neurodegenerative changes. Yet despite potential for convergence of the COVID-19 pandemic upon a pre- existing public health crisis of dementia, little research has been devoted to understanding the mechanistic overlap between these conditions or the potentially catastrophic public health consequences of their synergy. The proposed investigation will assess the neurobiological sequalae of COVID-19 in older adults along with their modification by sex, AD pathology, and AD genetic risk. Restriction spectrum imaging to measure brain microstructure and dynamic contrast-enhanced MRI to estimate BBB permeability will be conducted on adults aged 50 years or older with previous COVID-19 infection (CV) and disease-related cognitive impairment, and on uninfected healthy controls. Cognitive testing will be conducted at time of neuroimaging and annually for up to four additional years. AD polygenic hazard scores (PHS), estrogen and testosterone levels, and plasma p- tau181, will be measured for all participants, and lifetime estrogen exposure will be calculated for women. This project will test the hypotheses that CV exhibit greater BBB breakdown, microstructural damage, and more severe cognitive impairment and decline than controls (Aim 1). AD risk (Aim 2) and sex (Aim 3) are predicted to modify effects of COVID-19 on brain and cognitive measures, with more severe disease-related brain injury, BBB permeability, and cognitive decline for those with high PHS or abnormal p-tau181 and for women. In sex- stratified analyses, testosterone and estrogen are expected to correlate with brain injury, BBB breakdown, and cognitive deficits (Aim 3). This study will pioneer the most advanced diffusion and permeability MRI techniques to clarify the yet elusive neurobiological effects of COVID-19 underlying its cognitive symptoms in older adults at elevated risk for neurodegenerative changes. It will advance our understanding of the currently speculative synergy between COVID-19 and AD pathogenesis as well as the complex role of sex and hormonal regulation in COVID-19-related neurological sequalae.

PROJECT NARRATIVE This project will address a critical emerging public health concern by elucidating the cerebrovascular and microstructural brain changes following COVID-19 infection that may predispose aging adults to long-term cognitive impairment or neurodegenerative changes. By examining how COVID-19-related brain and cognitive measures differ by sex and are modified Alzheimer’s disease genetic risk and pathology, results are expected to help identify individuals at greatest risk for adverse COVID-19-related neurological outcomes and to guide personalized approaches for risk assessment and treatment. This project will support the mission of the NIH by clarifying how COVID-19 impacts neurobiological aging and may amplify an already grave public health crisis of age-related cognitive decline and dementia.