Ekaterina Rogaeva Reflects Upon the Genetic link between COVID-19 and Alzheimer’s Disease

The global outbreak of severe acute respiratory corona virus-2 causing coronavirus disease 2019 (COVID-19) has tested the worldwide population with a challenging time. In addition to the respiratory symptoms of COVID-19, about 30% of hospitalised patients develop neurological symptoms (e.g., ataxia, corticospinal tract signs, agitation, delirium, headache, cerebrovascular disease, epilepsy, loss of taste and smell) [5, 6]. The virus triggers infection by binding to angiotensin converting enzyme 2 (ACE2) [9], which is expressed in multiple tissues (e.g., lung, kidney, heart, and brain), and could in part be responsible for the complexity of COVID-19 symptoms. Of note, ACE2 activity is reduced in Alzheimer’s Disease (AD) in association with increasing Aβ and tau pathology [1].

Intriguingly, a recent UK study [8] revealed a genetic link between COVID-19 and apolipoprotein E (APOE), a known major risk factor for AD and related disorders. In the human genome, APOE has three main alleles (ε2, ε3, and ε4). The ε4-allele increases risk and lowers age at onset of AD; whereas the ε2-allele confers a protective benefit against AD [3]. The UK study reported that ε4/ε4-individuals have an increased risk of severe COVID-19 infection based on the observation that ε4/ε4-individuals were twice as likely to test positive for COVID-19 compared to ε3/ε3-individuals [8]. Notably, this association was independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes.

However, the UK study has some limitations [8]. The cohort size is modest (622 COVID-19 positive patients, including only 37 ε4/ε4-individuals); and validation in an independent dataset has not been conducted. Furthermore, data for ε2-individuals was not presented; it would be important to assess the potential protective effect of the ε2-allele in COVID-19 patients in future large studies. In addition, the measure of COVID-19 severity was based on a general consideration that during the peak outbreak in the UK, COVID-19 testing was mainly restricted to patients with clinical signs of infection, and therefore a positive test would be a marker of severe COVID-19 infection. Genetic architecture could contribute to the diversity in incidence and symptoms of COVID-19 among different ethnic groups. Hence, it would be important to conduct a systematic genome-wide investigation of factors influencing disease presentation in COVID-19 patients from different populations, with a special focus on genetic variants affecting expression of the ACE2 gene (receptor for the virus). The study of genes that are homologous to ACE2 and involved in the same pathway would also be valuable, since such genes could contribute to the severity of the viral infection [4]. For instance, gene structure between ACE2 and angiotensin I converting enzyme (ACE) has 60% similarity. Notably, our previous gene-candidate approach [2] and more recent genome-wide association study have demonstrated that ACE is genetically involved in AD [7].

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References

1 Kehoe PG, Wong S, Al Mulhim N, Palmer LE, Miners JS. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. Alzheimers Res Ther. 2016 Nov 25;8(1):50. Doi: 10.1186/s13195-016-0217-7

2 Farrer LA, Sherbatich T, Keryanov SA, Korovaitseva GI, Rogaeva EA, Petruk S, Premkumar S, Moliaka Y, Song YQ, Pei Yet al (2000) Association between angiotensin-converting enzyme and Alzheimer disease. Arch Neurol 57: 210-214 Doi 10.1001/archneur.57.2.210

3 Ghani M, Reitz C, St George-Hyslop P, Rogaeva E (2018) Genetic Complexity of Early-Onset Alzheimer’s Disease. In: Galimberti D, Scarpini E (eds) Neurodegenerative Diseases. Springer, Cham, City

4 Haghighi MM & Rogaeva E (review in preparation) Insights into gene family of ACE2 - the receptor for SARS-CoV-2 virus in COVID-19.

5 Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, Collange O, Boulay C, Fafi-Kremer S, Ohana Met al (2020) Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med: Doi 10.1056/NEJMc2008597

6 Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X, Li Y, Hu B. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020 Apr 10:e201127 Doi: 10.1001/jamaneurol.2020.1127.

7 Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, et al (2019) Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet 51: 414-430 Doi 10.1038/s41588-019-0358-2

8 Kuo CL, Pilling LC, Atkins JL, Masoli JAH, Delgado J, Kuchel GA, Melzer D (2020) APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. J Gerontol A Biol Sci Med Sci: Doi 10.1093/gerona/glaa131

9 Wan Y, Shang J, Graham R, Baric RS, Li F (2020) Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol 94: Doi 10.1128/JVI.00127-20