The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer’s Disease and Aging: A Review of Knowledge

Abstract

Coronavirus Disease 2019 (COVID-19) pandemic-triggered mortality is significantly higher in older than in younger populations worldwide. Alzheimer’s disease (AD) is related to aging and was recently reported to be among the major risk factors for COVID-19 mortality in older people. The symptomatology of COVID-19 indicates that lethal outcomes of infection rely on neurogenic mechanisms. The present review compiles the available knowledge pointing to the convergence of COVID-19 complications with the mechanisms of autonomic dysfunctions in AD and aging. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is prone to neuroinvasion from the lung along the vagus nerve up to the brainstem autonomic nervous centers involved in the coupling of cardiovascular and respiratory rhythms. The brainstem autonomic network allows SARS-CoV-2 to trigger a neurogenic switch to hypertension and hypoventilation, which may act in synergy with aging- and AD-induced dysautonomias, along with an inflammatory “storm”. The lethal outcomes of COVID-19, like in AD and unhealthy aging, likely rely on a critical hypoactivity of the efferent vagus nerve cholinergic pathway, which is involved in lowering cardiovascular pressure and systemic inflammation tone. We further discuss the emerging evidence supporting the use of 1) the non-invasive stimulation of vagus nerve as an additional therapeutic approach for severe COVID-19, and 2) the demonstrated vagal tone index, i.e., heart rate variability, via smartphone-based applications as a non-serological low-cost diagnostic of COVID-19. These two well-known medical approaches are already available and now deserve large-scale testing on human cohorts in the context of both AD and COVID-19.

Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories

“…In fact, the vagus nerve innervates most abdominal organs, including the lungs. Through the vagal sensory innervation of the alveolar epithelium, the virus could reach the dorsal vagal complex in the brainstem and generate multiple autonomic dysfunctions (Rangon et al, 2020 ). However, it has also been hypothesised that viral detection in CNS tissue can be due to contamination with blood rich in viral material, especially in cases of cerebrovascular damage (Al-Dalahmah et al, 2020 ).…”

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

“…Autopsy, animal, and organoid model studies show that, like SARS-CoV, SARS-CoV-2 is able to reach and infect cells of the CNS, infect neurons, and produce neuroinflammation ( Matschke et al, 2020 ; Song et al, 2020 ; Song et al, 2021 ). Indeed, SARS-CoV-2 may be capable of transport up and down nerves and neuronal axons ( Lima et al, 2020 ; Rangon et al, 2020 ; Song et al, 2020 ; Karuppan et al, 2021 ).…”

Wireless Heart Rate Variability in Assessing Community COVID-19

“…HRV has been described in this special HRV Horizons 2030 Frontiers series as follows: “HRV offers insights into humoral, neural, and neurovisceral processes in health and disorders of brain, body, and behavior but has yet to be fully potentiated in the digital age” (Owens, 2020 ). Building on a growing body of HRV data (Rangon et al, 2020 ; Whitelaw et al, 2020 ; Hirten et al, 2021 ), we propose use of a wearable high fidelity Oura sensor ring ( https://ouraring.com/blog/category/research-validation/ ) to acquire HRV, in addition to other physiological indicators, to track both pre-illness longitudinal baseline and an ongoing longitudinal Community assessment of those indicators associated with COVID-19 using algorithmic analysis and actionable feedback. While various aspects of this proposal have been used by investigators producing promising results at UC San Francisco (Smarr et al, 2020 ), UC San Diego/Scripps Research (Whitelaw et al, 2020 ), Stanford School of Medicine (Perez et al, 2019 ), Mt.…”