The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in over 0.7 billion infections globally. A significant portion of patients (estimated 10-15%) experience long-term symptoms known as Long-COVID syndrome, encompassing fatigue, respiratory issues, and neurological problems including cognitive impairment (brain fog). The incidence of dementia and psychiatric disorders is significantly higher in SARS-CoV-2 patients compared to those with influenza or other respiratory infections. Even mild COVID-19 cases can present with subclinical cognitive impairment. This review focuses on the molecular mechanisms underlying SARS-CoV-2's impact on the brain and memory, investigating the routes of viral invasion, the role of host factors (ACE2, NRP1, etc.), the consequences of syncytia formation, and the effects on brain regions crucial for memory storage. The review also explores the various factors contributing to Long-COVID and strategies for its prevention and mitigation.

The review draws upon a wide range of studies, including those investigating SARS-CoV-2 invasion routes (olfactory nerves, blood-brain barrier, optic nerve), ACE2 expression in the brain, the role of alternative receptors and co-factors, the impact of syncytia formation on brain cells, and the effects of SARS-CoV-2 on various brain regions associated with memory (hippocampus, neocortex, amygdala, etc.). The literature reviewed encompasses studies using brain organoids, animal models (non-human primates), and human patient data (MRI scans, cerebrospinal fluid analysis, post-mortem tissue examination). Studies on the immune response to SARS-CoV-2 infection, including cytokine production, autoantibody formation, and microclot formation are also included. The impact of Long-COVID on children's brain development and memory is also addressed based on existing literature.

This is a review article. The methodology involves a comprehensive literature search and review of published studies investigating the molecular mechanisms and clinical manifestations of SARS-CoV-2's long-term effects on the brain and memory. The authors systematically searched relevant databases for studies exploring various aspects of the topic, including: the routes of SARS-CoV-2 entry into the brain, the role of host receptors and factors in viral replication, the impact of syncytia formation, effects on brain regions associated with memory, the mechanisms by which SARS-CoV-2 affects memory, contributing factors to long COVID, and prevention strategies. The studies reviewed employed diverse methodologies such as in-vitro studies using human brain organoids, in-vivo studies using animal models, and clinical studies involving human patients with different disease severities and age groups. Information gathered from these studies was synthesized and analyzed to produce a comprehensive overview of the long-term effects of SARS-CoV-2 infection on brain and memory. The selection criteria included peer-reviewed articles published in reputable scientific journals.

SARS-CoV-2 can invade the brain through multiple routes: directly through olfactory nerves, hematogenously via the blood-brain barrier, and potentially through the optic nerve. ACE2, the primary SARS-CoV-2 receptor, is expressed in various brain regions, supporting viral replication. Alternative receptors and co-factors, such as NRP1 and CD147, also play a role. SARS-CoV-2 spike protein induces cell-cell fusion (syncytia), leading to cell death and potentially contributing to neurological symptoms. SARS-CoV-2 infection affects brain regions critical for memory storage, impacting both short-term and long-term memory. The mechanisms involve direct viral infection, immune dysfunction (cytokine storm), and potentially persistent infection. Long-COVID is associated with immune dysfunction, cytokine storms, syncytia formation, and autoantibodies, impacting brain and memory functions. Microclots and biopsychosocial factors may also contribute. Vaccination and non-pharmaceutical interventions are crucial for prevention. Early intervention with cytokine-blocking agents and cognitive remediation therapy may help manage cognitive deficits. Maintaining good health through exercise, proper sleep, and balanced nutrition is also important. The long-term effects of SARS-CoV-2 on children's developing brains are a significant concern.

The findings of this review highlight the significant long-term neurological consequences of SARS-CoV-2 infection, particularly its impact on brain structure and memory function. The various pathways of neuroinvasion, combined with the detrimental effects of viral replication and immune dysregulation, underscore the complexity of Long-COVID pathogenesis. While the direct role of viral infection within the brain remains a subject of ongoing investigation, the evidence points towards a multifactorial etiology. The impact of syncytia formation and the potential for persistent viral infection in immunological sanctuaries warrant further research. The findings emphasize the need for effective prevention strategies, including vaccination, and the exploration of therapeutic interventions to mitigate the long-term neurological effects of SARS-CoV-2 infection.

This review underscores the substantial and multifaceted long-term effects of SARS-CoV-2 infection on the human brain and memory. Multiple routes of viral entry, the contribution of host factors, the pathological consequences of syncytia, and the disruption of immune homeostasis all contribute to this complex issue. While prevention through vaccination and lifestyle choices is paramount, further research into the mechanisms of Long-COVID and the development of targeted therapeutic interventions is crucial, particularly regarding the vulnerable pediatric population. Future studies should focus on longitudinal analyses of brain changes, the development of sensitive biomarkers for early detection, and effective therapeutic approaches to alleviate the debilitating effects of Long-COVID.

This review is limited by the inherent nature of its retrospective design. The current body of research on Long-COVID is still evolving, and further studies are required to fully elucidate the pathogenesis and long-term consequences. The heterogeneity in study designs, sample sizes, and clinical endpoints across the studies included in this review may limit the generalizability of certain findings. Moreover, the biopsychosocial factors influencing Long-COVID are complex and difficult to quantify precisely, potentially leading to some uncertainty in the interpretation of their contribution.