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Severe COVID-19 in Alzheimer’s disease: APOE4’s fault again?

Severe COVID-19 in Alzheimer’s disease: APOE4’s fault again? Challenges have been recognized in healthcare of patients with Alzheimer’s disease (AD) in the COVID-19 pandemic, given a high infection and mortality rate of COVID-19 in these patients. This situation urges the identification of underlying risks and preferably biomarkers for evidence-based, more effective healthcare. Towards this goal, current literature review and network analysis synthesize available information on the AD-related gene APOE into four lines of mechanistic evidence. At a cellular level, the risk isoform APOE4 confers high infectivity by the underlying coronavirus SARS-CoV-2; at a genetic level, APOE4 is associated with severe COVID-19; at a pathway level, networking connects APOE with COVID-19 risk factors such as ACE2, TMPRSS2, NRP1, and LZTFL1; at a behavioral level, APOE4-associated dementia may increase the exposure to coronavirus infection which causes COVID-19. Thus, APOE4 could exert multiple actions for high infection and mortality rates of the patients, or generally, with COVID-19. Keywords: APOE4, Biomarker, Coronavirus, Comorbidity, Peripheral mechanisms, COVID-19 Background Genetic evidence for APOE4 involvement in the In the midst of the COVID-19 pandemic, patients with vulnerability for COVID-19 Alzheimer’s disease (AD), once infected by the under- There is evidence for the genetic contribution to comor- lying coronavirus SARS-CoV-2, are 5 times likely to die bidity of other brain disorders with COVID-19 [5]so of this infectious disease [1]. In the absence of effective that genetics may explain the high vulnerability of pa- treatment, a mechanistic understanding of how the pa- tients with AD as well. APOE4 is the most established tients with AD become a vulnerable target of COVID-19 genetic risk factor for late-onset AD. An in vitro study may guide evidence-based healthcare management and has suggested that cells expressing APOE4 are more vul- targeted therapeutics development. In the earlier litera- nerable to SARS-CoV-2 infection than those expressing ture, it was postulated that APOE4 (italic for gene), a the nonpathogenic isoform APOE3 [6]. Via induced genetic risk factor for AD [2], would be a biomarker for pluripotent stem cells (iPSC)-based in vitro technologies, severe COVID-19 [3]; others considered psychological cells with APOE4 allowed more significant SARS-CoV-2 and behavioral contributions [4]. This review aims to infection of artificially differentiated either neurons or capitalize on the evolving literature and database re- astrocytes than those with APOE3. Furthermore, APOE4 sources and seek a fundamental or molecular under- astrocytes infected with SARS-CoV-2 presented a more standing of the high vulnerability in patients with AD. severe cytopathogenic effect than APOE3 astrocytes, which could facilitate the progression and severity of COVID-19. This study indeed provided the first insight to a possible APOE-mediated mechanism for COVID-19 * Correspondence: zhicheng_lin@hms.harvard.edu 4 severity. It remained unknown how this genetic vulner- Laboratory for Psychiatric Neurogenomics, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA ability was achieved and more importantly what this Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 2 of 5 finding meant for a high infection rate in APOE4 car- APOE3, possibly via enhancing the receptors’ activities riers and increased COVID-19 mortality in the comorbid and facilitating the coronavirus entry. patients. The difference between APOE4 and APOE2/3 is Pathway support for a role of APOE4 in the caused by the single nucleotide polymorphism (SNP) severity of COVID-19 rs429358. This SNP carries two alleles, T and C, where To explore this possibility, we have used a pathway ana- T encodes a cystine (APOE3) and C encodes an arginine lysis approach in MetaCore as previously described [12]. (APOE4) at residue position 130. In APOE4 carriers, re- Results from this pathway analysis indeed support that duced expression levels of APOE in both brain and per- possibility by identifying a plausible ten-member net- ipheral systems suggested that this variant causes an work where all ten members have been implicated in increased risk not only for AD [7, 8], but also for sys- AD: APOE [13], ACE2 [14], CTNNB1 [15], NOTCH1 temic susceptibility to coronavirus infection. APOE4 has [16, 17], LZTFL1 [18], MMP1 [19], NRP1 [20], RELA a worldwide average frequency of 15%, according to the [21], SIRT1 [22], and MMP14 [19](left panel in Fig. 1). 1000 Genomes Project [9], meaning that approximately Among them, ACE2 and NRP1 are utilized by SARS- 2% of the worldwide population are homozygotes, equal CoV-2 in order to enter cells and cause COVID-19 [23, to the current 2% of the world population that have been 24]. ACE2 is almost undetectable and NRP1 has low ex- diagnosed with COVID-19. In fact, APOE is abundantly pression levels in the brain. For a better understanding expressed in cells of various peripheral systems including of the epidemiological finding, these functional genetic macrophages and epithelial cells of the lung [10, 11] and pathway findings may encourage and re-direct our which confers the most severe impact on coronavirus attention from the brain with AD to comorbid patients’ pathology. As an explanation, patients with APOE4- peripheral systems, where both receptors are well associated AD may carry higher vulnerability in their expressed and the coronavirus has an easy access, does peripheral organs such as the lung than those carrying extensive damages during the progression, and causes Fig. 1 Possible mechanisms of APOE4-mediated AD and COVID-19 comorbidity. Left panel: A ten-member network shared by both AD (all members) and COVID-19 (*), generated by using MetaCore. In the case of APOE4, reduced/altered APOE has three potential actions in this network alone: (1) disinhibition of ACE2, (2) transcriptional reduction of the protective LZTFL1, and (3) more indirect disinhibition of NRP1 via LZTF1, in exacerbation of COVID-19. Asterisks are for genetic association with severe COVID-19: APOE: rs429358 (APOE2/3 vs 4) p = 0.0026, OR = −10 1.31; ACE2: chr23:15564667 p = 0.0056, OR = 1.12; CTNNB1: chr3:41204313 p = 0.016, OR = 0.74; LZTFL1: chr3:45834967 p = 1.15 × 10 ,OR = 0.56; NOTCH1: chr9:136510909 p = 0.0092, OR = 0.87; MMP1: rs11621460 p = 0.010, OR = 0.84; NRP1: chr10:33292184 p = 0.00072, OR = 1.47; RelA: rs1049728 p = 0.0063, OR = 0.64 (II); SIRT1: rs12783242 p = 0.0019, OR = 0.78; where chromosome positions are based on HG38 in the absence of rs numbers; OR, odds ratio; II, adjusted with gender and age; all association signals are provided by the GWAS meta-analysis by Ellinghaus et al. Not shown here is the additional APOE-LRP1-PARP1-TMPRSS2 pathway (see text): LRP1: rs4759044 p = 0.023, OR = 0.89; PARP1: chr1:226405149 p = 0.0065, OR = 0.51 (II). Right panel: APOE4-based vulnerability for patients with COVID-19 and AD at double risk: attenuated protective behavior for exposure risk and APOE4-associated infection risk Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 3 of 5 multiorgan damage-triggered mortality of COVID-19. protective roles of both APOE and LZTFL1. That is, re- Of note, it has been experimentally shown that the cor- duced APOE levels, which have demonstrated to be as- onavirus (SARS-CoV) enters cells by binding to ACE2 sociated with the increased risk of AD, may disinhibit while ACE2 may recycle subsequently back to cell sur- ACE2, TMPRSS2, and NRP1 and consistently increase face after unloading of the virus [25]. Specifically, ACE2- the vulnerability to the coronavirus infection in the pa- related endocytosis, besides direct membrane fusion, has tients with AD. In fact, indirect activation of APOE by been proposed as an entry mechanism [26], consistent LZTFL1 via CTNNB1 (generic binding protein) and with the recent identification of the endosomal protein MPPs (metalloprotease) fits with their protections TMEM106B as another risk factor for the coronavirus against the fatal comorbidity. infection [27]. More interestingly, nine of the ten members in this Further pathway analyses found that SIRT1, the direct network, along with LRP1 and PARP1 in the TMPRSS2 target of APOE, might regulate TMEM106 through pathway, had nominal significance for genetic associa- binding to several AD-related transcription factors (e.g., tions indeed with the severity of COVID-19 (Fig. 1 le- FOXP3 [28], STAT1 [29], BMAL1 [30, 31], SIRT6 [32], gend for left panel), as revealed by the meta-analysis of and E2F1 [33]) but the specifics on these regulations and GWAS [18]. For APOE, it was rs429358 that encodes on how TMEM106B regulates coronavirus’ intracellular APOE4 (p = 0.0026), but not another nearby (only meta activity remain to be uncovered. Interestingly, FOXP3 138 bp away) SNP rs7412 C/T that differentiates the also bound to TMPRSS2 which encoded another cell nonpathogenic APOE2 vs 3 (Cys176Arg) (p = 0.73), meta surface risk factor for SARS-CoV-2 infection [23]. Also, that showed an association with severe COVID-19, se- reduced APOE could reduce LRP1 inhibition of the lectively supporting the underlying risk of APOE4 and TMPRSS2 activator PARP1, which in turn promotes the the in vitro experimental finding that there is an associ- coronavirus infection as well (detailed pathway not ation between APOE4 and COVID-19 infectivity. The shown) [34, 35]. Therefore, APOE might regulate the in- APOE networking had a 17.6-fold enrichment for associ- fectivity of SARS-CoV-2 in multiple ways. ations with severe COVID-19 based on p -values, meta Among the ten members, LZTFL1 represents the most comparing to the whole GWAS, pointing to a shared significant genetic risk factor for severe COVID-19 as molecular etiology. per findings from two genome-wide association studies It remains unknown how significant this pathway in- (GWAS) of severe COVID-19 [18, 36]. Specifically, a formation contributes to ACE2/TMPRSS2/NRP1-related minor allele of a SNP (G/GA, without a “rs” number yet) infection itself. Such information however encourages at chr3:45834967 in LZTFL1 was protective against pro- modeling analysis of human peripheral (epithelial and gression to severe forms of COVID-19. Together, immune) cells that bear the brunt of the coronavirus in- APOE4 may have tetrad action: it enhances ACE2 activ- fection for further clarification of the APOE4 mechan- ity by disinhibiting SIRT1 (Sirtuin 1, a generic enzyme), ism in COVID-19 development and progression. Even activates TMPRSS2 by the LRP1-PARP1 pathway, de- worse for AD, the molecular vulnerability can be fur- creases the LZTFL1 expression by inhibiting NOTCH1, thered by exposure-related behavioral disadvantage in and activates NRP1 via LZTFL1 indirectly, satisfying the the patients (right panel in Fig. 1). Fig. 2 Summary: coronavirus targets AD patients carrying APOE4 Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 4 of 5 Conclusion 4. Keng A, Brown EE, Rostas A, Rajji TK, Pollock BG, Mulsant BH, et al. Effectively caring for individuals with behavioral and psychological Comparing to two other isoforms, APOE4 is genetically symptoms of dementia during the COVID-19 pandemic. 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Martínez-Martínez AB, Torres-Perez E, Devanney N, del Moral R, Johnson LA, and MRS contributed to revision and finalization. The authors read and Arbones-Mainar JM. Beyond the CNS: the many peripheral roles of APOE. approved the final manuscript. Neurobiol Dis. 2020;138:104809. https://doi.org/10.1016/j.nbd.2020.104809. 12. Liu K, Zhao J, Chen C, Xu J, Bell RL, Hall FS, et al. Epistatic evidence for Authors’ information gender-dependant slow neurotransmission signalling in substance use NX is the President of Wuhan Red Cross Hospital and a neurologist; JL is a disorders: PPP1R12B versus PPP1R1B. EBioMedicine. 2020;61:103066. https:// Ph.D. student; XC is the head of the Neurology Department and a clinician; doi.org/10.1016/j.ebiom.2020.103066. MRS is the Director of the Nevada Institute of Personalized Medicine at 13. Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor UNLV; ZL is an associate neurobiologist. for Alzheimer’s disease. 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Severe COVID-19 in Alzheimer’s disease: APOE4’s fault again?

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Abstract

Challenges have been recognized in healthcare of patients with Alzheimer’s disease (AD) in the COVID-19 pandemic, given a high infection and mortality rate of COVID-19 in these patients. This situation urges the identification of underlying risks and preferably biomarkers for evidence-based, more effective healthcare. Towards this goal, current literature review and network analysis synthesize available information on the AD-related gene APOE into four lines of mechanistic evidence. At a cellular level, the risk isoform APOE4 confers high infectivity by the underlying coronavirus SARS-CoV-2; at a genetic level, APOE4 is associated with severe COVID-19; at a pathway level, networking connects APOE with COVID-19 risk factors such as ACE2, TMPRSS2, NRP1, and LZTFL1; at a behavioral level, APOE4-associated dementia may increase the exposure to coronavirus infection which causes COVID-19. Thus, APOE4 could exert multiple actions for high infection and mortality rates of the patients, or generally, with COVID-19. Keywords: APOE4, Biomarker, Coronavirus, Comorbidity, Peripheral mechanisms, COVID-19 Background Genetic evidence for APOE4 involvement in the In the midst of the COVID-19 pandemic, patients with vulnerability for COVID-19 Alzheimer’s disease (AD), once infected by the under- There is evidence for the genetic contribution to comor- lying coronavirus SARS-CoV-2, are 5 times likely to die bidity of other brain disorders with COVID-19 [5]so of this infectious disease [1]. In the absence of effective that genetics may explain the high vulnerability of pa- treatment, a mechanistic understanding of how the pa- tients with AD as well. APOE4 is the most established tients with AD become a vulnerable target of COVID-19 genetic risk factor for late-onset AD. An in vitro study may guide evidence-based healthcare management and has suggested that cells expressing APOE4 are more vul- targeted therapeutics development. In the earlier litera- nerable to SARS-CoV-2 infection than those expressing ture, it was postulated that APOE4 (italic for gene), a the nonpathogenic isoform APOE3 [6]. Via induced genetic risk factor for AD [2], would be a biomarker for pluripotent stem cells (iPSC)-based in vitro technologies, severe COVID-19 [3]; others considered psychological cells with APOE4 allowed more significant SARS-CoV-2 and behavioral contributions [4]. This review aims to infection of artificially differentiated either neurons or capitalize on the evolving literature and database re- astrocytes than those with APOE3. Furthermore, APOE4 sources and seek a fundamental or molecular under- astrocytes infected with SARS-CoV-2 presented a more standing of the high vulnerability in patients with AD. severe cytopathogenic effect than APOE3 astrocytes, which could facilitate the progression and severity of COVID-19. This study indeed provided the first insight to a possible APOE-mediated mechanism for COVID-19 * Correspondence: zhicheng_lin@hms.harvard.edu 4 severity. It remained unknown how this genetic vulner- Laboratory for Psychiatric Neurogenomics, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA ability was achieved and more importantly what this Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 2 of 5 finding meant for a high infection rate in APOE4 car- APOE3, possibly via enhancing the receptors’ activities riers and increased COVID-19 mortality in the comorbid and facilitating the coronavirus entry. patients. The difference between APOE4 and APOE2/3 is Pathway support for a role of APOE4 in the caused by the single nucleotide polymorphism (SNP) severity of COVID-19 rs429358. This SNP carries two alleles, T and C, where To explore this possibility, we have used a pathway ana- T encodes a cystine (APOE3) and C encodes an arginine lysis approach in MetaCore as previously described [12]. (APOE4) at residue position 130. In APOE4 carriers, re- Results from this pathway analysis indeed support that duced expression levels of APOE in both brain and per- possibility by identifying a plausible ten-member net- ipheral systems suggested that this variant causes an work where all ten members have been implicated in increased risk not only for AD [7, 8], but also for sys- AD: APOE [13], ACE2 [14], CTNNB1 [15], NOTCH1 temic susceptibility to coronavirus infection. APOE4 has [16, 17], LZTFL1 [18], MMP1 [19], NRP1 [20], RELA a worldwide average frequency of 15%, according to the [21], SIRT1 [22], and MMP14 [19](left panel in Fig. 1). 1000 Genomes Project [9], meaning that approximately Among them, ACE2 and NRP1 are utilized by SARS- 2% of the worldwide population are homozygotes, equal CoV-2 in order to enter cells and cause COVID-19 [23, to the current 2% of the world population that have been 24]. ACE2 is almost undetectable and NRP1 has low ex- diagnosed with COVID-19. In fact, APOE is abundantly pression levels in the brain. For a better understanding expressed in cells of various peripheral systems including of the epidemiological finding, these functional genetic macrophages and epithelial cells of the lung [10, 11] and pathway findings may encourage and re-direct our which confers the most severe impact on coronavirus attention from the brain with AD to comorbid patients’ pathology. As an explanation, patients with APOE4- peripheral systems, where both receptors are well associated AD may carry higher vulnerability in their expressed and the coronavirus has an easy access, does peripheral organs such as the lung than those carrying extensive damages during the progression, and causes Fig. 1 Possible mechanisms of APOE4-mediated AD and COVID-19 comorbidity. Left panel: A ten-member network shared by both AD (all members) and COVID-19 (*), generated by using MetaCore. In the case of APOE4, reduced/altered APOE has three potential actions in this network alone: (1) disinhibition of ACE2, (2) transcriptional reduction of the protective LZTFL1, and (3) more indirect disinhibition of NRP1 via LZTF1, in exacerbation of COVID-19. Asterisks are for genetic association with severe COVID-19: APOE: rs429358 (APOE2/3 vs 4) p = 0.0026, OR = −10 1.31; ACE2: chr23:15564667 p = 0.0056, OR = 1.12; CTNNB1: chr3:41204313 p = 0.016, OR = 0.74; LZTFL1: chr3:45834967 p = 1.15 × 10 ,OR = 0.56; NOTCH1: chr9:136510909 p = 0.0092, OR = 0.87; MMP1: rs11621460 p = 0.010, OR = 0.84; NRP1: chr10:33292184 p = 0.00072, OR = 1.47; RelA: rs1049728 p = 0.0063, OR = 0.64 (II); SIRT1: rs12783242 p = 0.0019, OR = 0.78; where chromosome positions are based on HG38 in the absence of rs numbers; OR, odds ratio; II, adjusted with gender and age; all association signals are provided by the GWAS meta-analysis by Ellinghaus et al. Not shown here is the additional APOE-LRP1-PARP1-TMPRSS2 pathway (see text): LRP1: rs4759044 p = 0.023, OR = 0.89; PARP1: chr1:226405149 p = 0.0065, OR = 0.51 (II). Right panel: APOE4-based vulnerability for patients with COVID-19 and AD at double risk: attenuated protective behavior for exposure risk and APOE4-associated infection risk Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 3 of 5 multiorgan damage-triggered mortality of COVID-19. protective roles of both APOE and LZTFL1. That is, re- Of note, it has been experimentally shown that the cor- duced APOE levels, which have demonstrated to be as- onavirus (SARS-CoV) enters cells by binding to ACE2 sociated with the increased risk of AD, may disinhibit while ACE2 may recycle subsequently back to cell sur- ACE2, TMPRSS2, and NRP1 and consistently increase face after unloading of the virus [25]. Specifically, ACE2- the vulnerability to the coronavirus infection in the pa- related endocytosis, besides direct membrane fusion, has tients with AD. In fact, indirect activation of APOE by been proposed as an entry mechanism [26], consistent LZTFL1 via CTNNB1 (generic binding protein) and with the recent identification of the endosomal protein MPPs (metalloprotease) fits with their protections TMEM106B as another risk factor for the coronavirus against the fatal comorbidity. infection [27]. More interestingly, nine of the ten members in this Further pathway analyses found that SIRT1, the direct network, along with LRP1 and PARP1 in the TMPRSS2 target of APOE, might regulate TMEM106 through pathway, had nominal significance for genetic associa- binding to several AD-related transcription factors (e.g., tions indeed with the severity of COVID-19 (Fig. 1 le- FOXP3 [28], STAT1 [29], BMAL1 [30, 31], SIRT6 [32], gend for left panel), as revealed by the meta-analysis of and E2F1 [33]) but the specifics on these regulations and GWAS [18]. For APOE, it was rs429358 that encodes on how TMEM106B regulates coronavirus’ intracellular APOE4 (p = 0.0026), but not another nearby (only meta activity remain to be uncovered. Interestingly, FOXP3 138 bp away) SNP rs7412 C/T that differentiates the also bound to TMPRSS2 which encoded another cell nonpathogenic APOE2 vs 3 (Cys176Arg) (p = 0.73), meta surface risk factor for SARS-CoV-2 infection [23]. Also, that showed an association with severe COVID-19, se- reduced APOE could reduce LRP1 inhibition of the lectively supporting the underlying risk of APOE4 and TMPRSS2 activator PARP1, which in turn promotes the the in vitro experimental finding that there is an associ- coronavirus infection as well (detailed pathway not ation between APOE4 and COVID-19 infectivity. The shown) [34, 35]. Therefore, APOE might regulate the in- APOE networking had a 17.6-fold enrichment for associ- fectivity of SARS-CoV-2 in multiple ways. ations with severe COVID-19 based on p -values, meta Among the ten members, LZTFL1 represents the most comparing to the whole GWAS, pointing to a shared significant genetic risk factor for severe COVID-19 as molecular etiology. per findings from two genome-wide association studies It remains unknown how significant this pathway in- (GWAS) of severe COVID-19 [18, 36]. Specifically, a formation contributes to ACE2/TMPRSS2/NRP1-related minor allele of a SNP (G/GA, without a “rs” number yet) infection itself. Such information however encourages at chr3:45834967 in LZTFL1 was protective against pro- modeling analysis of human peripheral (epithelial and gression to severe forms of COVID-19. Together, immune) cells that bear the brunt of the coronavirus in- APOE4 may have tetrad action: it enhances ACE2 activ- fection for further clarification of the APOE4 mechan- ity by disinhibiting SIRT1 (Sirtuin 1, a generic enzyme), ism in COVID-19 development and progression. Even activates TMPRSS2 by the LRP1-PARP1 pathway, de- worse for AD, the molecular vulnerability can be fur- creases the LZTFL1 expression by inhibiting NOTCH1, thered by exposure-related behavioral disadvantage in and activates NRP1 via LZTFL1 indirectly, satisfying the the patients (right panel in Fig. 1). Fig. 2 Summary: coronavirus targets AD patients carrying APOE4 Xiong et al. Alzheimer's Research & Therapy (2021) 13:111 Page 4 of 5 Conclusion 4. Keng A, Brown EE, Rostas A, Rajji TK, Pollock BG, Mulsant BH, et al. Effectively caring for individuals with behavioral and psychological Comparing to two other isoforms, APOE4 is genetically symptoms of dementia during the COVID-19 pandemic. 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Journal

Alzheimer's Research & TherapySpringer Journals

Published: Jun 12, 2021

Keywords: APOE4; Biomarker; Coronavirus; Comorbidity; Peripheral mechanisms; COVID-19

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