4 August 2020
We read a commentary by Naughton and colleagues published in your journal with extreme interest regarding the potential novel role of Coronavirus Disease-19 (COVID-19) in Alzheimer’s Disease (AD) . In addition, we also read a review by Fotuhi and colleagues in this journal, the neurological complications triggered by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) and the possible mechanism of the connection between SARS-Cov-2 and the brain . Their views are inspiring for neurologists who are concerned about the neurodegenerative diseases following COVID-19. As they said, developing effective treatment strategies for the COVID-19 epidemic is an urgent issue, however, we cannot ignore the long-term impact.
The SARS-Cov-2 emerged in China in late 2019 has become a global pandemic. In addition to acute respiratory tract infection, SARS-Cov-2 also shows neuroinvasiveness and can cause neurological symptoms such as delirium, headaches, and cognitive impairment. It has been reported that SARS-Cov-2 infection determines neurological signs in 36.4% of the patients, usually starting with smell and taste disorders. Recently, autopsies from China reported that SARS-Cov-2 was detected in the cerebrospinal fluid and frontal lobe samples of COVID-19 patients[4,5], which has attracted a lot of attention in neurology. In another study, ultrastructural analysis of the olfactory nerve, gyrus rectus, and brainstem at the level of the medulla observed severe and extensive tissue damage, involving the neurons, glia, nerve axons, and myelin sheath. Additionally, numerous particles referable to virions of SARS-Cov-2 were observed. According to that reports, the virus may enter the brain through the olfactory nerve which reinforces the hypothesis that the brain may be a reservoir site for SARS-Cov-2. Those findings prompted the researchers to consider whether SARS-Cov-2 will cause or exacerbates neurodegenerative diseases, such as AD.
As far as we know, infection with some pathogens may lead to cognitive impairment, dementia, and AD in particular. Several pathogens have been identified to contribute to the pathophysiology of AD, such as herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumonia, Helicobacter pylori, and spirochete. Although, these pathogens may require a certain genetic background (APOE 4) or risk factors (e.g., hypercholesterolemia, aging, hypertension, diabetes, or cerebrovascular disorder) to cause AD pathophysiology and pathogenesis. Moreover，convincing evidence suggests that neuroinflammation is a prominent feature of neurodegeneration and plays a vital role in AD pathology. Immune response and excessive inflammation in patients with COVID-19 may trigger or accelerate the development of AD. We are concerned that SARS-CoV-2 may have a long latency period in the central nervous systems. If this is the case, various non-specific inflammatory diseases may initiate or reactivate certain inflammatory or oxidative reactions in AD. These inflammatory responses and oxidative by-products may lead to amyloid plaque deposition and hippocampal damage. Given the widespread prevalence and neurotropism of SARS-Cov-2, will it be the next candidate virus? This should attract our attention seriously due to previous studies that have detected other coronaviruses in the central nervous systems of elderly people and patients with AD. Even though no direct evidence on AD pathophysiology caused by SARS-Cov-2 has been found so far, current evidence points in this research direction.
Currently, our medical interventions focused on acute treatment of the life-threatening consequences of COVID-19. However, cytokine storms and high levels of inflammation inside the brain are likely to have long-term neuropsychiatric consequences. Due to the current lack of understanding of the potential effects of SARS-Cov-2 on the nervous system, further studies and more pathological examinations of the brains of infected patients are required to elucidate this problem. Furthermore, neurologists and nurses should be given early reminders to follow-up on COVID-19 survivors; patients, especially elderly people, who recover from COVID-19 may subsequently develop AD. In addition, a prospective study is warranted to investigate the potential correlation between acute and subacute COVID-19 and long-term neurological sequelae, such as AD, in order to better prepare for potential complications.
Nanyang Liu, Hao Li
Institude of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical, Beijing 100091, P. R. China, E-mail: firstname.lastname@example.org
This study was supported by National Projects for Leading Professionals in Traditional Chinese Medicine (Qi Huang Scholar, No.02045003). The funder has no role in the study.
Declaration of personal interests: The authors have no conflicts of interest to disclose.
 Naughton SX, Raval U, Pasinetti GM (2020) Potential novel role of COVID-19 in Alzheimer's disease and preventative mitigation strategies. J Alzheimers Dis 76, 21-25.
 Fotuhi M, Mian A, Meysami S, Raji CA (2020) Neurobiology of COVID-19. J Alzheimers Dis 76, 3-19.
 Zubair AS, Mcalpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S (2020). Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol, doi: 10.1001/jamaneurol.2020.2065.
 Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, Ueno M, Sakata H, Kondo K, Myose N, Nakao A, Takeda M, Haro H, Inoue O, Suzuki-Inoue K, Kubokawa K, Ogihara S, Sasaki T, Kinouchi H, Kojin H, Ito M, Onishi H, Shimizu T, Sasaki Y, Enomoto N, Ishihara H, Furuya S, Yamamoto T, Shimada S (2020) A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis 94, 55-58.
 Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92, 699-702.
 Bulfamante G, Chiumello D, Canevini MP, Priori A, Mazzanti M, Centanni S, Felisati G (2020). First ultrastructural autoptic findings of SARS-Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol 86, 678-679.
 Honjo K, van Reekum R, Verhoeff NPLG (2009). Alzheimer's disease and infection: Do infectious agents contribute to progression of Alzheimer's disease? Alzheimers Dement 5, 348-360.
 Gomez-Pinedo U, Matias-Guiu J, Sanclemente-Alaman I, Moreno-Jimenez L, Montero-Escribano P (2020) SARS-CoV2 as a potential trigger of neurodegenerative diseases. Mov Disord 34, 1104-1105.