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Expression of SARS-CoV-2 entry receptor ACE2 in human brain and its association with Alzheimer’s disease and COVID-19

Molecular Psychiatry volume 30, pages 3257–3268 (2025)Cite this article

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Abstract

It is known that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19). It is widely reported that Alzheimer’s disease (AD) is associated with the highest risk of COVID-19 infection, hospitalization and mortality. However, it remains largely unclear about the link between AD and COVID-19. ACE2 is an entry receptor for SARS-CoV-2. We consider that there may be a link between AD and COVID-19 through the expression of ACE2. Here, we summarize recent findings about the ACE2 expression especially in AD and COVID-19, and shows that (1) ACE2 shows mRNA and protein expression in human brain tissues, especially in neurons and non-neuron cells; (2) low ACE2 mRNA and protein expression are sufficient for SARS-CoV-2 entry into the human brain through the neural route (olfactory and/or vagal) and the hematogenous route; (3) SARS-CoV-2 RNA and protein were detected in brains of COVID-19 patients; (4) SARS-CoV-2 infects and replicates in human brain dependent on ACE2; (5) SARS-CoV-2 viral RNA load shows a positive association with ACE2 mRNA levels and COVID-19 severity; (6) ACE2 shows increased expression in AD compared with controls in human brain; (7) ACE2 shows increased expression in COVID-19 compared with controls in human brain; (8) ACE2 expression levels affect COVID-19 outcomes. Together, ACE2 shows significantly increased mRNA and protein expression in AD compared with controls in human brain. Consequently, the increased expression of ACE2 would facilitate infection with SARS-CoV-2, and play a role in the context of COVID-19. These findings suggest that the expression of ACE2 may partly explain the link of AD with COVID-19 infection, hospitalization and mortality.

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Fig. 1: Box plots for the expression of ACE2 in different tissues in GTEx.
Fig. 2: Link between AD and COVID-19 through the expression of ARS-CoV-2 entry receptor ACE2.
Fig. 3: Single-nucleus transcriptomes of SARS-CoV-2 entry receptors ACE2, CTSL, DPP4 and NRP1 in the major human brain vascular and perivascular cell types from the cortex and hippocampus of 9 AD patients and 8 controls.
Fig. 4: Single-nucleus transcriptomes of SARS-CoV-2 entry receptors TMEM106B, TMPRSS2, TMPRSS4 and TPCN2 in the major human brain vascular and perivascular cell types from the cortex and hippocampus of 9 AD patients and 8 controls.

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All relevant data are within the paper. The authors confirm that all data underlying the findings are either fully available without restriction through consortia websites, or may be made available from consortia upon request.

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Acknowledgements

We thank the Genotype-Tissue Expression (GTEx) Project. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: https://www.gtexportal.org/home/ the GTEx Portal (GTEx Analysis Release V10 (dbGaP Accession phs000424.v10.p2)) on December 4, 2024.

Funding

This work was supported by funding from the National Key R&D Program of China (No. 2023YFC3605200, and 2023YFC3605202), National Science and Technology Major Project (2023ZD0505306), National Natural Science Foundation of China (No. 82471449, 82071212, and 82371305), Beijing Natural Science Foundation (No. JQ21022 and Z240021).

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Author notes

  1. These authors contributed equally: Sijie Li, Jingyi Sun.

Authors and Affiliations

  1. Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

    Sijie Li

  2. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China

    Sijie Li, Shan Gao & Ping Zhu

  3. Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China

    Jingyi Sun

  4. Tianjin Key Laboratory of Cerebrovascular and of Neurodegenerative Diseases, Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China

    He Li

  5. Center of Respiratory Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Acadamy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, Beijing, 100029, China

    Zhifa Han

  6. Chinese Institute for Brain Research, Beijing, China

    Tao Wang

  7. Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, No. 22, Wenchang Road, Wuhu, 241002, Anhui, China

    Yan Chen

  8. Dongying Branch Center of Collaborative Innovation Center for Brain Disorders, Shengli Oilfield Central Hospital, No. 31 Jinan Road, Dongying, 257034, Shandong, China

    Peiguang Yan, Mingxin Wang & Guiyou Liu

  9. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Key Laboratory of Hypoxia Translational Medicine, Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, National Engineering Center of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, 100069, China

    Guiyou Liu

  10. Clinical Medicine Translational Research Institute, Chengdu Fifth People’s Hospital, Geriatric Diseases Institute of Chengdu, The Second Clinical Medical College, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, No.33, Ma Shi Street, Chengdu, 611137, Sichuan, China

    Guiyou Liu

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  1. Sijie Li
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Contributions

GYL, SJL, JYS, PGY and MXW conceived and initiated the project. GYL, HL, SJL, JYS, ZFH, TW, SG, PZ, and YC systematically searched PubMed, Google Scholar, Web of Science, Scopus, and Embase to identify the potential articles, analyzed the data, and wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.

Corresponding authors

Correspondence to Peiguang Yan, Mingxin Wang or Guiyou Liu.

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The authors declare no competing interests.

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This article contains human participants collected by several studies performed by previous studies. All participants gave informed consent in all the corresponding original studies. Here, our study is based on the publicly available datasets, and not the individual-level data. Hence, ethical approval was not sought.

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Li, S., Sun, J., Li, H. et al. Expression of SARS-CoV-2 entry receptor ACE2 in human brain and its association with Alzheimer’s disease and COVID-19. Mol Psychiatry 30, 3257–3268 (2025). https://doi.org/10.1038/s41380-025-03006-z

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