Investigating the Contribution of Peripheral versus Central Nervous System Immune Dysfunction to Cognitive Aging

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Project Summary/Abstract The insurgence of coronavirus disease 2019 (COVID-19) has disproportionately affected the older adult population and raised numerous questions regarding long-term sequalae of the novel SARS-CoV-2 virus on late life clinical outcomes. The pathological aging milieu is characterized by a ‘primed’ inflammatory state, increased risk of Alzheimer’s disease-related protein deposition, and greater vulnerability to systemic infections. We propose that the heterogeneity of clinical outcomes related to SARS-CoV-2 exposure may stem from variability in the “host” immune milieu and the presence of AD-related pathology, which may interface to negatively impact cognitive trajectories. As such, the overarching hypothesis of our administrative supplement is that older adults who are exposed to SARS-CoV-2 virus will experience greater cognitive decline, with worse outcomes noted in individuals with greater AD-related pathology and higher levels of systemic inflammatory markers. The existing infrastructure of the parent R01 provides a critical platform to appraise the effect of SARS-CoV-2 on aging outcomes, as our awarded grant funds the ascertainment of biospecimens [blood; CSF], analyses of Alzheimer’s Disease-related pathology (i.e., Aß1-42; phosphorylated tau; neurofilament light chain [NfL]) and analyses of inflammatory markers in 180 older adults over two time points. In this administrative supplement, we propose to evaluate antibody levels (i.e., presence or absence) to SARS-CoV-2 in serum at baseline and 2-year follow-up in the parent R01 cohort. SARS-CoV-2 exposure is associated with both symptomatic and asymptomatic disease; to enrich the parent R01 cohort for the likelihood of SARS-CoV-2 exposure, we will preferentially recruit 20 additional older adults with a history of confirmed (i.e., RT-PCR test) COVID-19 disease. We will address the following Aims: to determine whether exposure to SARS-CoV-2 exacerbates memory decline in community-dwelling older adults (Aim 1); and to elucidate whether associations between SARS-CoV-2 exposure and memory outcomes are influenced by the presence of Alzheimer’s Disease pathology and baseline immune status (Aim 2). We believe that the proposed study is significant to the cognitive neuroscience of immune aging; by clarifying the role of virus exposure on cognitive outcomes in late life, we will be poised to understand long-term neurological implications of SARS-CoV-2 on cognition and Alzheimer’s disease pathology in community-dwelling older adults, which may ultimately guide interventions for vulnerable populations.