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Advanced Neurology SARS-CoV-2 mechanisms of neurological impact

interacting serine/threonine kinase 1, have been identified neurons. Aβ interferes with synaptic transmission, while
in COVID-19-affected microglia, revealing distinct yet hyperphosphorylated tau disrupts nutrient transport
overlapping inflammatory pathways between COVID-19 within neurons. Both proteins activate microglia, leading
and neurodegenerative conditions. 157 to chronic inflammation and reduced brain volume. AD
Neurodegeneration has been associated with is the leading cause of dementia, manifesting in cognitive
inflammatory factors secreted by activated microglia, decline, memory loss, impaired judgment, and changes in
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including TNF-α and IL-1β. These pro-inflammatory personality, mood, and behavior.
cytokines impair microglial endocytosis of pathological 7.2. Shared roles of apolipoprotein E4 and NLR family
Aβ and tau proteins, exacerbating neuronal damage. In pyrin domain containing 3 inflammasome in AD and
contrast, anti-inflammatory microglia secrete cytokines neurodegenerative consequences of COVID-19
such as IL-2, IL-4, IL-10, and TGF-β, which promote repair
and recovery of learning and memory functions through During the COVID-19 pandemic, individuals with AD were
multiple signaling pathways (Table 4). 146,158 Understanding five times more likely to die from COVID-19 compared to
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the regulatory mechanisms that modulate microglial those without AD. The apolipoprotein E4 (APOE4) gene,
activation and their shift toward an anti-inflammatory a major risk factor for AD, has been identified as a potential
phenotype could provide new therapeutic targets for biomarker for severe COVID-19. 160,162 Specifically, the
mitigating CI. apolipoprotein E (APOE) ɛ4 allele has been implicated
as a susceptibility factor for both AD and COVID-19
Both astrocytes and microglia play pivotal roles in the (Table 4). 163-165 Research has shown that individuals with
neuroinflammatory responses observed in COVID-19. the APOE ɛ4/ɛ4 genotype face a higher risk of severe
Their activation not only mirrors processes seen in COVID-19 and are more likely to test positive compared
neurodegenerative diseases like AD but also introduces to those with the APOE ɛ3/ɛ3 genotype. 162
unique inflammatory pathways related to SARS-CoV-2
infection. The interaction between microglia and The APOE genotype plays a critical role in susceptibility
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astrocytes, along with their impact on neuronal survival to pathogens in various infectious diseases. APOE
and function, represents a key area for future research. proteins, which serve as receptors for viruses like
Understanding the regulatory mechanisms that modulate herpesvirus and hepatitis C, may also act as receptors
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glial activation in response to SARS-CoV-2 could inform for SARS-CoV-2. Pre-existing conditions such as
potential therapeutic strategies for mitigating long-term dementia and delirium increase the risk of severe
CI in COVID-19 survivors. Further studies exploring the COVID-19 outcomes. Both SARS-CoV-2 and AD lead to
molecular crosstalk between microglia and astrocytes may neurocognitive disorders, anxiety, excessive fatigue, and
pave the way for novel interventions aimed at reducing the olfactory dysfunction. Autopsies of COVID-19 patients
neurotoxic effects of COVID-19. have revealed widespread brain inflammation and
degeneration, even in those without prior neurological
7. Inflammatory pathways linking long symptoms. Studies have highlighted gene overlaps between
COVID to neurodegeneration in AD AD markers and genes upregulated during COVID-19
infection. 23,168 Inflammatory biomarkers, such as IL-6,
7.1. Neurological symptoms in long COVID and AD TNF, galectin-3, and IL-1 have, been proposed as shared
Given the multisystemic nature of long COVID, characterized prognostic indicators for both SARS-CoV-2 infection and
by the persistence or emergence of symptoms beyond the AD. 169
acute phase of infection, numerous hypotheses have been The activation of the NLR family pyrin domain
proposed to elucidate its underlying pathophysiological containing 3 (NLRP3) inflammasome, a crucial
mechanisms. The neurological symptoms associated with component of the immune system, has been linked to both
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long COVID, such as insomnia, fatigue, brain fog, anosmia, tau aggregation and neurodegeneration in the context of
memory loss, depression, and anxiety, bear a striking SARS-CoV-2 infection. The NLRP3 inflammasome
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resemblance to those observed in AD. 160,161 This overlap plays a pivotal role in regulating inflammatory responses,
suggests potential shared mechanisms between long and its dysregulation can contribute to neuronal damage
COVID and AD, prompting further investigation into how and cognitive decline. Furthermore, it is hypothesized
viral infections may influence long-term brain function and that SARS-CoV-2 may trigger the production of
neurodegeneration (Table 4). Aβ, an antimicrobial peptide, thereby potentially
AD is characterized by the accumulation of Aβ plaques heightening the risk of AD in COVID-19 patients
and hyperphosphorylated tau proteins, which damage (Table 4). 171-173 The potential link between SARS-CoV-2,

Volume 4 Issue 2 (2025) 22 doi: 10.36922/an.4909