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Advanced Neurology

REVIEW ARTICLE
SARS-CoV-2 and its long-term neurological

impact: Unraveling the mechanisms of
neurodegeneration and cognitive decline

Moawiah M. Naffaa *
1,2
1 Department of Cell Biology, Duke University School of Medicine, Durham, North Carolina, United
States of America
2 Department of Psychology and Neuroscience, Trinity College of Arts and Sciences, Duke University,
Durham, North Carolina, United States of America

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible
for coronavirus disease 2019 (COVID-19), is associated with neurological effects that
persist beyond the acute phase, collectively referred to as post-acute sequelae of
SARS-CoV-2 infection (PASC) or “long COVID.” This article discusses the neurological
impacts of PASC, which can occur regardless of the initial illness’s severity. Studies
indicate that most patients continue to experience symptoms for at least 3 months
post-infection. Long-term effects include neurocognitive deficits, sleep disturbances,
and the exacerbation of pre-existing conditions. Proposed mechanisms underlying
these effects include neuroinflammation, microvascular damage, and autoimmune
*Corresponding author: responses, while direct viral neuroinvasion remains a topic of ongoing debate.
Moawiah M Naffaa
(moawiah.naffaa@duke.edu) SARS-CoV-2 may also worsen pre-existing neurological disorders and increase the
risk of developing neurodegenerative diseases such as Alzheimer’s disease (AD) and
Citation: Naffaa MM. SARS-CoV-2
and its long-term neurological Parkinson’s disease. The article highlights the need for longitudinal studies to better
impact: Unraveling the mechanisms understand the variability in outcomes and the mechanisms driving these persistent
of neurodegeneration and cognitive effects. In addition, it explores the inflammatory pathways linking long COVID to
decline. Adv Neurol. 2025;4(2):12-40.
doi: 10.36922/an.4909 AD. Both conditions are characterized by chronic inflammation, activation of shared
markers such as the NLR family pyrin domain containing 3 inflammasome, and
Received: September 23, 2024 alterations in amyloid-beta production. The apolipoprotein E4 gene, a known risk
1st revised: November 25, 2024 factor for AD, is also associated with more severe COVID-19 outcomes. Neuroimaging
2nd revised: December 5, 2024 studies reveal brain changes in COVID-19 survivors, particularly in regions related
to cognition and memory, further emphasizing the need for long-term research to
Accepted: December 26, 2024 assess the potential role of long COVID in exacerbating neurodegenerative diseases.
Published online: January 9, 2025
Copyright: © 2025 Author(s). Keywords: SARS-CoV-2; Long COVID; Neurodegenerative diseases; Cognitive decline;
This is an Open-Access article
distributed under the terms of the Inflammatory pathways; Autoimmune responses; Alzheimer’s disease; Neuro-post-acute
Creative Commons Attribution sequelae of SARS-CoV-2 infection
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience 1. Introduction
Publishing remains neutral with Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome
regard to jurisdictional claims in
published maps and institutional coronavirus 2 (SARS-CoV-2) virus, has predominantly been linked to severe respiratory
affiliations. outcomes, such as acute respiratory distress syndrome (ARDS), respiratory failure,

Volume 4 Issue 2 (2025) 12 doi: 10.36922/an.4909