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.