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Review
. 2025 May 26;26(11):5102.
doi: 10.3390/ijms26115102.

The Molecular Mechanisms of Cognitive Dysfunction in Long COVID: A Narrative Review

Elena Popa  1   2 , Andrei Emilian Popa  3 , Mihaela Poroch  1   2 , Vladimir Poroch  1 , Monica Iuliana Ungureanu  1   2 , Ana Maria Slanina  1   2 , Agnes Bacusca  1   2 , Elena Adorata Coman  1   2
Affiliations
Review

The Molecular Mechanisms of Cognitive Dysfunction in Long COVID: A Narrative Review

Elena Popa et al. Int J Mol Sci. .

Abstract

Cognitive dysfunction represents one of the most persistent and disabling features of Long COVID, yet its molecular underpinnings remain incompletely understood. This narrative review synthesizes current evidence on the pathophysiological mechanisms linking SARS-CoV-2 infection to long-term neurocognitive sequelae. Key processes include persistent neuroinflammation, blood-brain barrier (BBB) disruption, endothelial dysfunction, immune dysregulation, and neuroendocrine imbalance. Microglial activation and cytokine release (e.g., IL-6, TNF-α) promote synaptic dysfunction and neuronal injury, while activation of inflammasomes such as NLRP3 amplifies CNS inflammation. Vascular abnormalities, including microthrombosis and BBB leakage, facilitate the infiltration of peripheral immune cells and neurotoxic mediators. Hypothalamic-pituitary-adrenal axis dysfunction and reduced vagal tone further exacerbate systemic inflammation and autonomic imbalance. Biomarkers such as GFAP, NFL, IL-6, and S100B have been associated with both neuroinflammation and cognitive symptoms. Notably, transcriptomic signatures in Long COVID overlap with those observed in Alzheimer's disease, highlighting shared pathways involving tau dysregulation, oxidative stress, and glial reactivity. Understanding these mechanisms is critical for identifying at-risk individuals and developing targeted therapeutic strategies. This review underscores the need for longitudinal research and integrative biomarker analysis to elucidate the molecular trajectory of cognitive impairment in Long COVID.

Keywords: cognitive dysfunction; long-COVID; neuroinflammation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of cognitive dysfunction in Long COVID.
Figure 2
Figure 2
Neuroinflammatory and vascular pathways in Long COVID.
Figure 3
Figure 3
Disruption of the VEGF-A/NRP1 signaling axis by SARS-CoV-2.
Figure 4
Figure 4
Molecular crosstalk between Long COVID and Alzheimer’s disease pathogenesis.
See this image and copyright information in PMC

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