Long-term effects of SARS-CoV-2 infection on human brain and memory

The review addresses how SARS-CoV-2 infection leads to long-term neurological and cognitive effects, including memory impairment, in a substantial subset (approximately 10–15%) of infected individuals. Despite widespread vaccination, highly transmissible variants such as Omicron have driven large case numbers and breakthrough infections. The paper synthesizes evidence on the routes of neuroinvasion, effects on brain structure and function, and mechanisms (direct infection, immune dysregulation, syncytia formation, persistent infection, microclots, and psychosocial factors) that may underpin Long-COVID symptoms like fatigue, hyposmia, dyspnea, headache, myalgia, anxiety, and “brain fog.” It highlights increased risks of dementia and psychiatric disorders post-COVID-19 compared with other respiratory infections and frames the need to understand and mitigate long-term brain and memory consequences.

- Routes of neuroinvasion: Evidence supports multiple potential routes for SARS-CoV-2 to reach the brain, including direct spread from the nasal cavity via olfactory nerves; hematogenous dissemination with crossing of the blood-brain barrier (via ACE2-mediated transcellular entry, paracellular disruption of tight junctions, or intracellular carriage); and a possible ocular route via the optic nerve. - ACE2 and brain susceptibility: ACE2 is detected in human brain tissues (mature choroid plexus, cortical gray matter, olfactory bulb). In human brain organoids, ACE2 blockade inhibits infection and SARS-CoV-2 replicates with increasing titers, supporting susceptibility. - Additional host factors: Beyond ACE2, attachment/co-receptors including heparan sulfate, CD147 (debated as a direct receptor), AXL, C-type lectins (DC-SIGN/L-SIGN), phosphatidylserine receptors, and Neuropilin-1 (NRP1) may facilitate entry, including in olfactory and cerebral regions. - Neurological effects and imaging: Long-COVID commonly includes neurological/psychiatric symptoms. UK Biobank MRI analyses indicate greater brain atrophy and loss of gray matter in infected individuals (mostly mild cases), though with limitations (older cohort). SARS-CoV-2 RNA is rarely detected in CSF, suggesting immune-mediated mechanisms are important; however, brain organoids and non-human primate studies show brain infection is possible. Increased parkinsonism and Alzheimer’s-like neuropathology have been reported post-COVID-19. - Spike-mediated syncytia: Spike–ACE2-driven cell–cell fusion forms syncytia in tissues, associated with severe disease, immune dysregulation, lymphocyte internalization, and apoptosis/pyroptosis. Neuronal and glial fusion has been observed in models, linking viral fusion mechanisms to neurodegeneration risk. - Memory-related brain regions: Memory involves hippocampus, amygdala, neocortex, retrosplenial and prefrontal cortices, basal ganglia, and cerebellum. SARS-CoV-2 proteins/RNA have been detected in cortical neurons, endothelial cells, and astrocytes, with astrocyte infection linked to neuronal dysfunction. Proinflammatory cytokines (IL-6, TNFα, IL-1β) can impair working memory and cognition and cross/affect the BBB via microglial activation. - Children: Long-COVID occurs in children, including short-term memory problems and cognitive issues, with particular concern given critical brain development stages. CNS infection has been documented in a 14-month-old child; symptoms can persist >4 months even after mild disease. - Mechanisms impacting memory: Direct brain infection and spike-induced syncytia can cause cell death and inflammation. Indirect mechanisms include systemic cytokine responses, T-cell activation at CNS borders, and autoantibodies (∼10% of severe cases) targeting blood vessels, heart, and brain. Persistent infection in anatomical sanctuaries has been documented across patient groups, and spike S1 alone can induce neuroinflammatory responses. - Risk factors: Cytokine storm, syncytia, autoantibodies, microclots (amyloid fibrin), and biopsychosocial factors may contribute to Long-COVID symptomatology and persistence. - Prevention/mitigation: Vaccination, non-pharmaceutical interventions, need for antivirals, early cytokine-blocking strategies, cognitive remediation, and lifestyle/nutritional supports (exercise, sleep, diet; vitamins, zinc, magnesium; fermented vegetables) are discussed as potential approaches to reduce Long-COVID burden.

- Long-COVID prevalence: Approximately 10–15% of SARS-CoV-2 patients experience persistent symptoms, including cognitive and memory issues; about 10% of adults with SARS-CoV-2 appear to have Long-COVID. - Neuroinvasion routes: Evidence supports olfactory, hematogenous (crossing a dysregulated BBB), and ocular routes for brain entry. - Neural susceptibility: ACE2 is present in human brain regions; organoids support viral replication, and ACE2 blockade reduces infection. NRP1 and other cofactors may facilitate CNS infectivity. - Brain structure/function changes: MRI data from 785 participants (majority >50 years) show greater brain atrophy and gray matter loss post-infection, even in mild cases; cognitive impairments are frequently reported after mild-to-moderate disease. - Direct and indirect mechanisms: SARS-CoV-2 can infect neurons/astrocytes and induce Alzheimer’s-like pathology in models; cytokines IL-6, TNFα, IL-1β can disrupt working memory and cognition via microglial activation and BBB interactions; spike S1 alone can provoke neuroinflammatory/behavioral responses. - Syncytia pathology: Spike–ACE2-mediated cell–cell fusion forms syncytia that drive apoptosis/pyroptosis, immune dysregulation, and may contribute to neurodegeneration; neuronal and glial fusion has been observed in experimental systems. - Autoimmunity and persistence: Around 10% of severe COVID-19 cases exhibit autoantibodies against host proteins (including in brain/vasculature); persistent viral RNA/proteins have been detected for months in various patient groups, potentially sustaining inflammation and symptoms. - Children affected: Long-COVID and short-term memory problems are reported in children; CNS infection documented in a 14-month-old; symptoms can persist >4 months after mild disease, with potential developmental impacts. - Risk modifiers: Microclots (amyloid fibrin) may trap proinflammatory proteins and contribute to failed fibrinolysis; biopsychosocial stressors correlate with symptom burden in some cohorts. - Mitigation strategies: Vaccination and NPIs reduce transmission; proposed approaches include antivirals, early cytokine blockade to prevent later depressive symptoms, cognitive remediation therapy, and lifestyle/nutritional optimization (exercise, sleep, diet; vitamins, zinc, magnesium).

The synthesis indicates that SARS-CoV-2 can affect the brain and memory through multiple, complementary pathways. Direct neuroinvasion is biologically plausible given ACE2/NRP1 expression and organoid/primate data, but rare CSF viral RNA in patients suggests that indirect mechanisms—systemic and CNS immune activation, cytokine signaling, and autoimmunity—play major roles in many cases. Spike-mediated syncytia and persistent antigen/RNA may drive prolonged neuroinflammation and neuronal dysfunction. Structural brain changes and cognitive deficits, observed even after mild infections, underscore the public health significance. The review highlights heterogeneous evidence, age-related considerations, and the need for preventive measures (vaccination, NPIs), early immunomodulation, cognitive rehabilitation, and supportive lifestyle/nutrition to mitigate long-term neurological sequelae. It emphasizes gaps in understanding the relative contributions of direct infection versus immune-mediated effects across disease severities and populations (including children) and calls for further mechanistic and longitudinal studies.

This review consolidates molecular and clinical evidence that SARS-CoV-2 can produce long-term neurological consequences affecting brain structure and memory via direct infection, immune dysregulation (cytokines, autoantibodies), spike-induced syncytia, persistent infection, microclots, and biopsychosocial factors. It outlines potential strategies to reduce Long-COVID burden: vaccination, non-pharmaceutical interventions, development and deployment of antivirals, targeted immunomodulation, cognitive remediation, and lifestyle/nutritional optimization. The authors stress that key questions remain regarding the mechanisms and risk stratification of Long-COVID brain effects, particularly in children and those with mild disease, and advocate for more coordinated, longitudinal, and mechanistic research to clarify pathogenesis and refine prevention and treatment.

- Imaging cohort limitations: The UK Biobank MRI study predominantly included older adults (∼97% >50 years), limiting generalizability and necessitating caution in interpretation. - Detection constraints: Rare detection of SARS-CoV-2 RNA in CSF of patients suggests that direct CNS infection may be underdetected or not the predominant cause in many cases; brain tissue data often come from severe/late-stage cases. - Heterogeneity and confounding: Variability in disease severity, timing, and comorbidities complicates attribution of cognitive symptoms to direct infection versus immune or psychosocial mechanisms; some studies report weak correlations between acute severity and Long-COVID symptom burden. - Mechanistic gaps: The relative contributions of direct neuroinvasion, systemic immune responses, autoantibodies, microclots, and psychosocial factors remain incompletely defined; more studies are needed to elucidate causal pathways and long-term outcomes.