There is a fundamental gap in our understanding of the neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Neuro-PASC consists in a wide array of symptoms affecting patient’s cognition and quality of life, as well as their ability to work. Up to 85% of Neuro-PASC patients complain of severe fatigue and 33% from insomnia. Of particular interest, subjective impression of fatigue correlates with low cognitive performance. A major obstacle to our understanding of one key aspect of Neuro-PASC pathogenesis is the complex interplay between sleep difficulties, profound fatigue and cognitive dysfunction presented by those patients. A key gap in our knowledge is the lack of data on the impact of Neuro-PASC in older adults, a population who are vulnerable for sleep disruption, fatigue, and cognitive dysfunction, and whether they are at increased risk for early onset of Alzheimer’s or other types of dementia. The overall objective of this supplement application is to leverage the research infrastructure of the parent project “An Epidemiologic Study of Disparities in Sleep and Cognition in Older Adults (DISCO)” to characterize sleep-wake disturbances, fatigue, and cognitive dysfunction in older adults with Neuro-PASC and decipher their immunopathogenic mechanisms. Our preliminary data indicate that Neuro-PASC patients have cognitive dysfunction, sleep disturbance and broad dysfunction in memory T cell generation against SARS-CoV-2 proteins and response to vaccination. The emerging immunologic picture in Neuro-PASC is consistent with dysregulation of T cell function is the setting of a persistent infection in hidden reservoirs. Since SARS-CoV-2 binds angiotensin converting enzyme -2 (ACE-2) receptors located on endothelial cells, this may result in an endotheliitis affecting the central nervous system, leading to alteration of sleep/wakefulness centers. In addition, there is ample evidence that sleep disruption has a detrimental impact on cellular immune responses, especially on regulatory T cells (Tregs). We hypothesize that sleep and circadian rhythm disruption and associated fatigue affects cognitive abilities in older Neuro-PASC patients. Moreover, poor sleep may have a compounding effect on the alterations of the cellular immune response to SARS-CoV-2, leading to an altered function of Tregs and development of autoimmunity, which may be a key long-term mechanism of Neuro-PASC. The rationale is that the proposed studies will enable us to understand a central aspect of Neuro-PASC pathogenesis in older adults and open new avenues to develop therapeutic and preventive interventions. We will test our hypothesis by pursuing the following Specific Aim: Aim 1: Characterize the pathogenic mechanisms of Neuro-PASC in adults ≥ 65 yo. We will determine the interplay of sleep and circadian rhythm disruption and T cell dysregulation on cognitive dysfunction in non-hospitalized Neuro-PASC patients ≥ 65 yo. The proposed supplement is ...