IMPORTANCE: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. OBJECTIVE: To determine whether rare missense variants on APOE are associated with AD risk. DESIGN, SETTING, AND PARTICIPANTS: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. MAIN OUTCOMES AND MEASURES: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. RESULTS: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. CONCLUSIONS AND RELEVANCE: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

1st Department of Neurology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

1st Department of Neurology Medical School Aristotle University of Thessaloniki Thessaloniki Greece

Aging Research Center Department of Neurobiology Care Sciences and Society Karolinska Institutet and Stockholm University Stockholm Sweden

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands

Alzheimer Research Center and Memory Clinic Andalusian Institute for Neuroscience Málaga Spain

Alzheimer's Centre Reina Sofia CIEN Foundation Madrid Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Department Hospital Clinic Barcelona Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Service of Neurology Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain

Centre for Memory Disturbances Lab of Clinical Neurochemistry Section of Neurology University of Perugia Perugia Italy

Centre for Neurodegenerative Disorders Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Centro de Biología Molecular Severo Ochoa Universidad Autónoma de Madrid Madrid Spain

Charité Universitätsmedizin Berlin Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute of Psychiatry and Psychotherapy Berlin Germany

CHU de Bordeaux Pole santé publique Bordeaux France

Clinic of Neurology UH Alexandrovska Medical University Sofia Sofia Bulgaria

Cluster of Excellence Cellular Stress Responses in Aging Associated Diseases University of Cologne Cologne Germany

Complex Genetics of Alzheimer's Disease Group VIB Center for Molecular Neurology VIB Antwerp Belgium

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Biomedical Surgical and Dental Sciences University of Milan Milan Italy

Department of Child and Adolescent Psychiatry and Psychotherapy Psychiatric University Hospital Zurich University of Zurich Zurich Switzerland

Department of Clinical Biochemistry Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Genetics VU University Medical Centre Amsterdam the Netherlands

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience Vrije University Amsterdam the Netherlands

Department of Epidemiology ErasmusMC Rotterdam the Netherlands

Department of Geriatric Psychiatry Central Institute of Mental Health Mannheim Faculty Mannheim University of Heidelberg Heidelberg Germany

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zurich Switzerland

Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Ontario Canada

Department of Neurodegenerative Diseases and Geriatric Psychiatry University Hospital Bonn Bonn Germany

Department of Neurology 2 B Sant Pau Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Department of Neurology and Neurological Sciences Stanford University Palo Alto California

Department of Neurology Bordeaux University Hospital Bordeaux France

Department of Neurology ErasmusMC Rotterdam the Netherlands

Department of Neurology Hospital Universitario Donostia San Sebastian Spain

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Neuroscience Rita Levi Montalcini University of Torino Torino Italy

Department of Neuroscience Università Cattolica del Sacro Cuore Rome Italy

Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston Texas

Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases UT Health San Antonio The University of Texas Health Science Center at San Antonio

Department of Psychiatry and Psychotherapy Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

Department of Psychiatry Psychosomatics and Psychotherapy Center of Mental Health University Hospital of Würzburg Würzburg Germany

Department of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden

Department of Radiology and Nuclear Medicine ErasmusMC Rotterdam the Netherlands

Depatamento de Especialidades Quirúrgicas Bioquímica e Inmunología Facultad de Medicina Universidad de Málaga Málaga Spain

Division of Psychological Medicine and Clinical Neuroscience School of Medicine Cardiff University Cardiff United Kingdom

Estudios en Neurociencias y Sistemas Complejos CONICET HEC UNAJ Universidad Nacional Arturo Jauretche Florencio Varela Argentina

Faculty of Medicine University of Lisbon Lisbon Portugal

Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Fundació Docència i Recerca MútuaTerrassa Terrassa Spain

German Center for Neurodegenerative Diseases Berlin Germany

German Center for Neurodegenerative Diseases Bonn Germany

German Center for Neurodegenerative Diseases Goettingen Germany

German Center for Neurodegenerative Diseases Magdeburg Germany

German Center for Neurodegenerative Diseases Munich Germany

Inserm Bordeaux Population Health Research Center UMR 1219 University of Bordeaux ISPED CIC 1401 EC Université de Bordeaux Bordeaux France

Institut de Recerca Biomedica de Lleida Lleida Spain

Institut du Cerveau Paris Brain Institute Paris France

Institute for Regenerative Medicine University of Zürich Zurich Switzerland

Institute for Stroke and Dementia Research University Hospital Ludwig Maximilian University of Munich Munich Germany

Institute for Urban Public Health University Hospital of University Duisburg Essen Essen Germany

Institute of Biomedicine University of Eastern Finland Joensuu Kuopio Finland

Institute of Clinical Medicine Neurology University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Cognitive Neurology and Dementia Research Otto von Guericke University Magdeburg Germany

Institute of Gerontology and Geriatrics Department of Medicine and Surgery University of Perugia Perugia Italy

Institute of Human Genetics University of Bonn School of Medicine University Hospital Bonn Bonn Germany

Institute of Neurology Catholic University of the Sacred Heart Rome Italy

Institute of Social Medicine Occupational Health and Public Health University of Leipzig Leipzig Germany

Instituto de Investigacion Sanitaria 'Hospital la Paz' Madrid Spain

Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

Interdisciplinary Department of Medicine Geriatric Medicine and Memory Unit University of Bari Aldo Moro Bari Italy

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

Krembil Brain Institute University Health Network Toronto Ontario Canada

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

Laboratory for Advanced Hematological Diagnostics Department of Hematology and Stem Cell Transplant Vito Fazzi Hospital Lecce Italy

Laboratory of Neurogenetics Born Bunge Institute Antwerp Belgium

Laboratory of Neuropsychiatry IRCCS Santa Lucia Foundation Rome Italy

LVR Hospital Essen Department of Psychiatry and Psychotherapy Medical Faculty University of Duisburg Essen Essen Germany

Maastricht University Department of Psychiatry and Neuropsychologie Alzheimer Center Limburg Maastricht the Netherlands

Medical University of Vienna Department of Psychiatry and Psychotherapy Vienna Austria

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Prague Czech Republic

Memory Disorders Unit Department of Neurology Hospital Universitari Mutua de Terrassa Terrassa Spain

Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

Munich Cluster for Systems Neurology Munich Germany

Networking Research Center on Neurodegenerative Diseases Instituto de Salud Carlos 3 Madrid Spain

Neurodegenerative Diseases Unit Fondazione IRCCS Ca' Granda Ospedale Policlinico Milan Italy

Neurological Tissue Bank Hospital Clinic IDIBAPS Barcelona Spain

Neurology San Gerardo Hospital Monza and University of Milano Bicocca Milan Italy

Neurology Service Marqués de Valdecilla University Hospital Santander Spain

Neurology Unit IRCCS Fondazione Policlinico Universitario A Gemelli Rome Italy

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Neurosciences and Signaling Group Institute of Biomedicine Department of Medical Sciences University of Aveiro Aveiro Portugal

Neurosciences Area Instituto Biodonostia San Sebastian Spain

Normandie Université UNIROUEN Inserm U1245 and CHU Rouen Department of Genetics and CNR MAJ Rouen France

NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Nuffield Department of Population Health Oxford University Oxford United Kingdom

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

Quantitative Sciences Unit Department of Medicine Stanford University Palo Alto California

Research Center and Memory Clinic Fundació ACE Institut Català de Neurociències Aplicades Universitat Internacional de Catalunya Barcelona Spain

School of Biosciences and Veterinary Medicine University of Camerino Camerino Italy

School of Medicine Cardiff University Cardiff United Kingdom

Taub Institute for Research in Alzheimer's Disease and the Aging Brain The Gertrude H Sergievsky Center Department of Neurology Columbia University New York New York

Technical University of Munich School of Medicine Klinikum rechts der Isar Department of Psychiatry and Psychotherapy Munich Germany

Translational Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

Unidad Clínica de Enfermedades Infecciosas y Microbiología Hospital Universitario de Valme Sevilla Spain

Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Seville Spain

Unidad Mixta de Neurologia Genètica Instituto de Investigación Sanitaria La Fe Valencia Spain

Unit for Hereditary Dementias Theme Aging Karolinska University Hospital Solna Stockholm Sweden

Unit of Neurology University of Parma Parma Italy

Unitat de Genètica Molecular Institut de Biomedicina de València CSIC Valencia Spain

Unitat Trastorns Cognitius Hospital Universitari Santa Maria de Lleida Lleida Spain

Université de Lille Inserm 1172 CHU Clinical and Research Memory Research Centre of Distalz Lille France

Université de Paris EA 4468 APHP Hôpital Broca Paris France

Université Paris Saclay CEA Centre National de Recherche en Génomique Humaine Evry France

University Bordeaux Inserm Bordeaux Population Health Research Center Bordeaux France

University of Lille Inserm CHU Lille Institut Pasteur de Lille U1167 RID AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement Lille France

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

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Zobrazit více v PubMed

Bellenguez C, Küçükali F, Jansen I, et al. . New insights on the genetic etiology of Alzheimer’s and related dementia. medRxiv. Preprint posted online December 14, 2020. doi:10.1101/2020.10.01.20200659 DOI

de Rojas I, Moreno-Grau S, Tesi N, et al. ; EADB contributors; GR@ACE study group; DEGESCO consortium; IGAP (ADGC, CHARGE, EADI, GERAD); PGC-ALZ consortia . Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nat Commun. 2021;12(1):3417. doi:10.1038/s41467-021-22491-8 PubMed DOI PMC

Corder EH, Saunders AM, Risch NJ, et al. . Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994;7(2):180-184. doi:10.1038/ng0694-180 PubMed DOI

Corder EH, Saunders AM, Strittmatter WJ, et al. . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921-923. doi:10.1126/science.8346443 PubMed DOI

Ridge PG, Hoyt KB, Boehme K, et al. ; Alzheimer’s Disease Genetics Consortium (ADGC) . Assessment of the genetic variance of late-onset Alzheimer’s disease. Neurobiol Aging. 2016;41:200.e13-200.e20. doi:10.1016/j.neurobiolaging.2016.02.024 PubMed DOI PMC

Morris JC, Roe CM, Xiong C, et al. . APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010;67(1):122-131. doi:10.1002/ana.21843 PubMed DOI PMC

Castellano JM, Kim J, Stewart FR, et al. . Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011;3(89):89ra57. doi:10.1126/scitranslmed.3002156 PubMed DOI PMC

Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron. 2019;101(5):820-838. doi:10.1016/j.neuron.2019.01.056 PubMed DOI PMC

Mak ACY, Pullinger CR, Tang LF, et al. . Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol. 2014;71(10):1228-1236. doi:10.1001/jamaneurol.2014.2011 PubMed DOI PMC

Le Guen Y, Belloy ME, Eger SJ, et al. . APOE missense variant R145C is associated with increased Alzheimer’s disease risk in African ancestry individuals with the APOE E3/E4 genotype. medRxiv. Preprint posted online October 26, 2021. doi:10.1101/2021.10.20.21265141 DOI

Arboleda-Velasquez JF, Lopera F, O’Hare M, et al. . Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019;25(11):1680-1683. doi:10.1038/s41591-019-0611-3 PubMed DOI PMC

Liu CC, Murray ME, Li X, et al. . APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Sci Transl Med. 2021;13(613):eabc9375. doi:10.1126/scitranslmed.abc9375 PubMed DOI PMC

Medway CW, Abdul-Hay S, Mims T, et al. . ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener. 2014;9(1):11. doi:10.1186/1750-1326-9-11 PubMed DOI PMC

Taliun D, Harris DN, Kessler MD, et al. ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium . Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Nature. 2021;590(7845):290-299. doi:10.1038/s41586-021-03205-y PubMed DOI PMC

Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. APOE and dementia—resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020;16(12):1624-1637. doi:10.1002/alz.12165 PubMed DOI PMC

Beecham GW, Bis JC, Martin ER, et al. . The Alzheimer’s Disease Sequencing Project: study design and sample selection. Neurol Genet. 2017;3(5):e194. doi:10.1212/NXG.0000000000000194 PubMed DOI PMC

Weiner MW, Aisen PS, Jack CR Jr, et al. ; Alzheimer’s Disease Neuroimaging Initiative . The Alzheimer’s Disease Neuroimaging Initiative: progress report and future plans. Alzheimers Dement. 2010;6(3):202-11.e7. doi:10.1016/j.jalz.2010.03.007 PubMed DOI PMC

Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS. Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res. 2012;9(6):646-663. doi:10.2174/156720512801322663 PubMed DOI PMC

Kunkle BW, Grenier-Boley B, Sims R, et al. ; Alzheimer Disease Genetics Consortium (ADGC); European Alzheimer’s Disease Initiative (EADI); Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE); Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES) . Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414-430. doi:10.1038/s41588-019-0358-2 PubMed DOI PMC

Kunkle BW, Schmidt M, Klein HU, et al. ; Writing Group for the Alzheimer’s Disease Genetics Consortium (ADGC) . Novel Alzheimer disease risk loci and pathways in African American individuals using the African Genome Resources Panel: a meta-analysis. JAMA Neurol. 2021;78(1):102-113. doi:10.1001/jamaneurol.2020.3536 PubMed DOI PMC

Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4(1):7. doi:10.1186/s13742-015-0047-8 PubMed DOI PMC

Karczewski KJ, Francioli LC, Tiao G, et al. ; Genome Aggregation Database Consortium . The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434-443. doi:10.1038/s41586-020-2308-7 PubMed DOI PMC

Le Guen Y, Belloy ME, Napolioni V, et al. ; Alzheimer’s Disease Neuroimaging Initiative . A novel age-informed approach for genetic association analysis in Alzheimer’s disease. Alzheimers Res Ther. 2021;13(1):72. doi:10.1186/s13195-021-00808-5 PubMed DOI PMC

Le Guen Y, Napolioni V, Belloy ME, et al. . Common X-chromosome variants are associated with Parkinson disease risk. Ann Neurol. 2021;90(1):22-34. doi:10.1002/ana.26051 PubMed DOI PMC

Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26(22):2867-2873. doi:10.1093/bioinformatics/btq559 PubMed DOI PMC

Chen CY, Pollack S, Hunter DJ, Hirschhorn JN, Kraft P, Price AL. Improved ancestry inference using weights from external reference panels. Bioinformatics. 2013;29(11):1399-1406. doi:10.1093/bioinformatics/btt144 PubMed DOI PMC

Auton A, Brooks LD, Durbin RM, et al. ; 1000 Genomes Project Consortium . A global reference for human genetic variation. Nature. 2015;526(7571):68-74. doi:10.1038/nature15393 PubMed DOI PMC

Bis JC, Jian X, Kunkle BW, et al. ; Alzheimer’s Disease Sequencing Project . Whole exome sequencing study identifies novel rare and common Alzheimer’s-associated variants involved in immune response and transcriptional regulation. Mol Psychiatry. 2020;25(8):1859-1875. doi:10.1038/s41380-018-0112-7 PubMed DOI PMC

Gogarten SM, Sofer T, Chen H, et al. . Genetic association testing using the GENESIS R/Bioconductor package. Bioinformatics. 2019;35(24):5346-5348. doi:10.1093/bioinformatics/btz567 PubMed DOI PMC

Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496-509. doi:10.1080/01621459.1999.10474144 DOI

Conomos MP, Miller MB, Thornton TA. Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genet Epidemiol. 2015;39(4):276-293. doi:10.1002/gepi.21896 PubMed DOI PMC

Conomos MP, Laurie CA, Stilp AM, et al. . Genetic diversity and association studies in US Hispanic/Latino populations: applications in the Hispanic Community Health Study/Study of Latinos. Am J Hum Genet. 2016;98(1):165-184. doi:10.1016/j.ajhg.2015.12.001 PubMed DOI PMC

Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1-48. doi:10.18637/jss.v036.i03 PubMed DOI

Huang Y, Weisgraber KH, Mucke L, Mahley RW. Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’s disease. J Mol Neurosci. 2004;23(3):189-204. doi:10.1385/JMN:23:3:189 PubMed DOI

Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72(pt A):3-12. doi:10.1016/j.nbd.2014.08.025 PubMed DOI PMC

Harris FM, Brecht WJ, Xu Q, et al. . Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A. 2003;100(19):10966-10971. doi:10.1073/pnas.1434398100 PubMed DOI PMC

Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Wang C, Huang Y. C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-β (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice. Proc Natl Acad Sci U S A. 2011;108(10):4236-4241. doi:10.1073/pnas.1018381108 PubMed DOI PMC

Huang YA, Zhou B, Wernig M, Südhof TC. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell. 2017;168(3):427-441.e21. doi:10.1016/j.cell.2016.12.044 PubMed DOI PMC

Choy N, Raussens V, Narayanaswami V. Inter-molecular coiled-coil formation in human apolipoprotein E C-terminal domain. J Mol Biol. 2003;334(3):527-539. doi:10.1016/j.jmb.2003.09.059 PubMed DOI

Westerlund JA, Weisgraber KH. Discrete carboxyl-terminal segments of apolipoprotein E mediate lipoprotein association and protein oligomerization. J Biol Chem. 1993;268(21):15745-15750. doi:10.1016/S0021-9258(18)82318-3 PubMed DOI

Flowers SA, Rebeck GW. APOE in the normal brain. Neurobiol Dis. 2020;136:104724. doi:10.1016/j.nbd.2019.104724 PubMed DOI PMC

Dyer CA, Cistola DP, Parry GC, Curtiss LK. Structural features of synthetic peptides of apolipoprotein E that bind the LDL receptor. J Lipid Res. 1995;36(1):80-88. doi:10.1016/S0022-2275(20)39756-X PubMed DOI

Weisgraber KH, Shinto LH. Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. impact on receptor binding activity. J Biol Chem. 1991;266(18):12029-12034. doi:10.1016/S0021-9258(18)99060-5 PubMed DOI

Minami SS, Cordova A, Cirrito JR, et al. . ApoE mimetic peptide decreases Abeta production in vitro and in vivo. Mol Neurodegener. 2010;5:16. doi:10.1186/1750-1326-5-16 PubMed DOI PMC

Minagawa H, Gong JS, Jung CG, et al. . Mechanism underlying apolipoprotein E (ApoE) isoform-dependent lipid efflux from neural cells in culture. J Neurosci Res. 2009;87(11):2498-2508. doi:10.1002/jnr.22073 PubMed DOI PMC

Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry. 2018;83(4):347-357. doi:10.1016/j.biopsych.2017.03.003 PubMed DOI PMC

Williams T, Borchelt DR, Chakrabarty P. Therapeutic approaches targeting apolipoprotein E function in Alzheimer’s disease. Mol Neurodegener. 2020;15(1):8. doi:10.1186/s13024-020-0358-9 PubMed DOI PMC