ABSTRACT Cognitive impairment is a major symptom among patients with post-acute sequelae of COVID-19. Older individuals and those with dementia risk factors are particularly at risk. In our own prospective study of 4,491 hospitalized COVID-19 patients, the median age was 65 years, 606 (14%) developed new neurological disorders (most commonly encephalopathy) during hospitalization, indicating a population at high risk for development of Alzheimer’s Disease or Related-Dementia (AD/ADRD). Of this group, 48% of patients who were cognitively normal pre-COVID had abnormal telephone MoCA scores (<18) 6-months post hospital discharge. We identified significant elevations in plasma biomarkers of neurodegeneration/AD including total tau, p-tau-181, UCH-L1, neurofilament light chain (NfL) and GFAP in hospitalized COVID-19 patients who developed encephalopathy compared to those who did not. These biomarkers significantly correlated with IL-6, CRP, ferritin and D-Dimer measures of inflammation. We hypothesize that older subjects with COVID-19, in particular those with new post-COVID subjective or objective cognitive abnormalities, will have increased plasma and radiographic AD/ADRD biomarkers, and a greater likelihood of abnormal cognitive testing and progression to Alzheimer’s disease or related dementias over time. We will enroll 3 groups of patients aged ≥60 years including: 1) SARS-CoV-2 positive subjects who have a new subjective or objective cognitive symptoms ≤6 month from index SARS-CoV-2 infection (COVID+Cog+) 2) SARS-CoV-2 positive subjects without subjective or objective cognitive symptoms ≤6 month from infection (COVID+Cog-); and 3) SARS-CoV-2 negative, neurologically/cognitively normal subjects, enrolled in the NYU ADRC Clinical Core (Controls). We will exclude individuals with a history of MCI or AD/ADRD prior to SARS-CoV-2 infection. Our primary outcome will be the differences in trajectories of global cognition/function (Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]) over the 5-year study across the 3 groups. Secondary outcomes will include: differences in plasma and radiographic AD/ADRD biomarkers over time compared across the 3 groups. Aim 1: Characterize and compare cognitive and neuropsychological abnormalities at enrollment and over time (every 12 months), among: COVID+Cog+, COVID+Cog- and controls using the CDR-SB, and Uniform Data Set Version 3. Aim 2: Characterize and compare plasma AD/ADRD-related biomarkers of neurodegeneration, inflammation and BBB dysfunction at enrollment and over time (every 12 months), among COVID+Cog+, COVID+Cog- and controls. Aim 3: Characterize and compare AD/ADRD neuroimaging biomarkers in COVID+Cog+, COVID+Cog- and controls at enrollment and over time (every 18 months) using 3T MRI. Collectively, these studies will elucidate predisposing risk factors and biomarkers for COVID-related cognitive abnormalities, provide mechanistic insights into underlying pathogenesis, and provide data on long-term outcomes, including the development of AD/ADRD- related disorders.

We hypothesize that older subjects with COVID-19, in particular those with new post-COVID subjective or objective cognitive abnormalities, will have increased plasma and radiographic AD/ADRD biomarkers, and a greater likelihood of abnormal cognitive testing and progression to Alzheimer’s disease or related dementias over time. Our proposed studies will elucidate predisposing risk factors and biomarkers for COVID-related cognitive abnormalities, provide mechanistic insights into underlying pathogenesis, and provide data on long- term outcomes, including the development of AD/ADRD-related disorders.