Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Courtney M Kloske¹, Michael E Belloy^{2

3

4}, Elizabeth E Blue^{5

6}, Gregory R Bowman⁷, Maria C Carrillo¹, Xiaoying Chen⁸, Ornit Chiba-Falek⁹, Albert A Davis¹⁰, Gilbert Di Paolo¹¹, Francesca Garretti^{12

13}, David Gate¹⁴, Lesley R Golden^{15

16}, Jay W Heinecke¹⁷, Joachim Herz¹⁸, Yadong Huang^{19

20}, Costantino Iadecola²¹, Lance A Johnson^{15

16}, Takahisa Kanekiyo²², Celeste M Karch²³, Anastasia Khvorova²⁴, Sascha J Koppes-den Hertog^{25

26}, Bruce T Lamb²⁷, Paige E Lawler^{4

28}, Yann Le Guen^{29

30}, Alexandra Litvinchuk⁸, Chia-Chen Liu²², Simin Mahinrad¹, Edoardo Marcora³¹, Claudia Marino³², Danny M Michaelson³³, Justin J Miller^{7

34}, Josh M Morganti^{16

35}, Priyanka S Narayan³⁶, Michel S Naslavsky^{37

38}, Marlies Oosthoek³⁹, Kapil V Ramachandran^{40

41

42}, Abhirami Ramakrishnan¹⁴, Ana-Caroline Raulin⁴³, Aiko Robert^{25

26}, Rasha N M Saleh^{44

45}, Claire Sexton¹, Nilomi Shah⁴⁶, Francis Shue⁴³, Isabel J Sible⁴⁷, Andrea Soranno⁴⁸, Michael R Strickland⁴, Julia Tcw^{49

50}, Manon Thierry⁵¹, Li-Huei Tsai⁵², Ryan A Tuckey⁵³, Jason D Ulrich⁸, Rik van der Kant^{25

26}, Na Wang⁵⁴, Cheryl L Wellington⁵⁵, Stacie C Weninger⁵⁶, Hussein N Yassine⁵⁷, Na Zhao²², Guojun Bu⁵⁸, Alison M Goate⁵⁹, David M Holtzman⁸

Affiliations

¹ Alzheimer's Association, Chicago, Illinois, USA.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, Palo Alto, California, USA.
³ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, St. Louis, Missouri, USA.
⁵ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁶ Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.
⁷ Departments of Biochemistry & Biophysics and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
⁹ Division of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁰ Department of Neurology Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, Missouri, USA.
¹¹ Denali Therapeutics Inc., San Francisco, California, USA.
¹² Ronald M. Loeb Center for Alzheimer's Disease, New York, New York, USA.
¹³ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁵ Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
¹⁶ Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
¹⁷ Department of Medicine, University of Washington, UV Medicine, Seattle, Washington, USA.
¹⁸ Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.
²⁰ Department of Neurology, University of California, San Francisco, California, USA.
²¹ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
²² Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
²³ Department of Psychiatry, Washington University in St Louis, St. Louis, Missouri, USA.
²⁴ RNA Therapeutic Institute, UMass Chan Medical School, Worcester, Massachusetts, USA.
²⁵ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, USA.
²⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, USA.
²⁷ Stark Neurosciences Research Institute Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁸ The Tracy Family SILQ Center, Washington University School of Medicine, Indianapolis, Indiana, USA.
²⁹ Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁰ Institut du Cerveau-Paris Brain Institute-ICM, Paris, France.
³¹ Department of Genetics and Genomic Sciences, Nash Family Department of Neuroscience, Icahn Genomics Institute; Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³² Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts, USA.
³³ Sagol School of Neuroscience Tel Aviv University, Tel Aviv, Israel.
³⁴ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA.
³⁵ Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
³⁶ Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Center for Alzheimer's and Related Dementias (CARD), National Institutes of Health, Maryland, USA.
³⁷ Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, Rua do Matao, São Paulo, Brazil.
³⁸ Hospital Israelita Albert Einstein, Avenida Albert Einstein, São Paulo, Brazil.
³⁹ Neurochemistry Laboratory, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
⁴⁰ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
⁴¹ Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁴² Department of Neuroscience, Columbia University Vagelos College of Physicians and Surgeons, New York, USA.
⁴³ Mayo Clinic Florida, Jacksonville, Florida, USA.
⁴⁴ Norwich Medical School, University of East Anglia, UK Clinical and Chemical Pathology, Norfolk, UK.
⁴⁵ Faculty of Medicine, Alexandria University, Alexandria Governorate, Egypt.
⁴⁶ Lexeo Therapeutics, New York, New York, USA.
⁴⁷ University of Southern California, Los Angeles, California, USA.
⁴⁸ Washington University in Saint Louis, St. Louis, Missouri, USA, St. Louis, Missouri, USA.
⁴⁹ Department of Pharmacology, Physiology & Biophysics, Chobanian and Avedisian School of Medicine, Boston University, Boston, Massachusetts, USA.
⁵⁰ Bioinformatics Program, Faculty of Computing & Data Sciences, Boston University, Boston, Massachusetts, USA.
⁵¹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
⁵² Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁵³ Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵⁴ Mayo Clinic Rochester, Rochester, Minnesota, USA.
⁵⁵ Djavad Mowafaghian Centre for Brain Health Department of Pathology and Laboratory Medicine International Collaboration on Repair Discoveries School of Biomedical Engineering University of British Columbia, Vancouver, Canada.
⁵⁶ FBRI, Massachusetts, USA.
⁵⁷ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁵⁸ Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
⁵⁹ Department of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 39031528
PMCID: PMC11497726
DOI: 10.1002/alz.13877

Review

Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Courtney M Kloske et al. Alzheimers Dement. 2024 Sep.

. 2024 Sep;20(9):6590-6605.

doi: 10.1002/alz.13877. Epub 2024 Jul 19.

Authors

Affiliations

¹ Alzheimer's Association, Chicago, Illinois, USA.
² Department of Neurology and Neurological Sciences, Stanford University, Stanford, Palo Alto, California, USA.
³ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, USA.
⁴ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, St. Louis, Missouri, USA.
⁵ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁶ Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.
⁷ Departments of Biochemistry & Biophysics and Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
⁹ Division of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁰ Department of Neurology Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, Missouri, USA.
¹¹ Denali Therapeutics Inc., San Francisco, California, USA.
¹² Ronald M. Loeb Center for Alzheimer's Disease, New York, New York, USA.
¹³ Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁵ Department of Physiology, University of Kentucky, Lexington, Kentucky, USA.
¹⁶ Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
¹⁷ Department of Medicine, University of Washington, UV Medicine, Seattle, Washington, USA.
¹⁸ Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹⁹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.
²⁰ Department of Neurology, University of California, San Francisco, California, USA.
²¹ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.
²² Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
²³ Department of Psychiatry, Washington University in St Louis, St. Louis, Missouri, USA.
²⁴ RNA Therapeutic Institute, UMass Chan Medical School, Worcester, Massachusetts, USA.
²⁵ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, Amsterdam, USA.
²⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, Amsterdam, USA.
²⁷ Stark Neurosciences Research Institute Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁸ The Tracy Family SILQ Center, Washington University School of Medicine, Indianapolis, Indiana, USA.
²⁹ Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁰ Institut du Cerveau-Paris Brain Institute-ICM, Paris, France.
³¹ Department of Genetics and Genomic Sciences, Nash Family Department of Neuroscience, Icahn Genomics Institute; Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³² Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts, USA.
³³ Sagol School of Neuroscience Tel Aviv University, Tel Aviv, Israel.
³⁴ Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA.
³⁵ Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
³⁶ Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Center for Alzheimer's and Related Dementias (CARD), National Institutes of Health, Maryland, USA.
³⁷ Human Genome and Stem-cell Research Center, Biosciences Institute, University of São Paulo, Rua do Matao, São Paulo, Brazil.
³⁸ Hospital Israelita Albert Einstein, Avenida Albert Einstein, São Paulo, Brazil.
³⁹ Neurochemistry Laboratory, Department of Laboratory Medicine, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.
⁴⁰ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA.
⁴¹ Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁴² Department of Neuroscience, Columbia University Vagelos College of Physicians and Surgeons, New York, USA.
⁴³ Mayo Clinic Florida, Jacksonville, Florida, USA.
⁴⁴ Norwich Medical School, University of East Anglia, UK Clinical and Chemical Pathology, Norfolk, UK.
⁴⁵ Faculty of Medicine, Alexandria University, Alexandria Governorate, Egypt.
⁴⁶ Lexeo Therapeutics, New York, New York, USA.
⁴⁷ University of Southern California, Los Angeles, California, USA.
⁴⁸ Washington University in Saint Louis, St. Louis, Missouri, USA, St. Louis, Missouri, USA.
⁴⁹ Department of Pharmacology, Physiology & Biophysics, Chobanian and Avedisian School of Medicine, Boston University, Boston, Massachusetts, USA.
⁵⁰ Bioinformatics Program, Faculty of Computing & Data Sciences, Boston University, Boston, Massachusetts, USA.
⁵¹ Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, New York, USA.
⁵² Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
⁵³ Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵⁴ Mayo Clinic Rochester, Rochester, Minnesota, USA.
⁵⁵ Djavad Mowafaghian Centre for Brain Health Department of Pathology and Laboratory Medicine International Collaboration on Repair Discoveries School of Biomedical Engineering University of British Columbia, Vancouver, Canada.
⁵⁶ FBRI, Massachusetts, USA.
⁵⁷ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁵⁸ Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
⁵⁹ Department of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 39031528
PMCID: PMC11497726
DOI: 10.1002/alz.13877

Abstract

Introduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.

Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function.

Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field.

Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine.

Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

Keywords: APOE; Alzheimer's disease; apolipoprotein E; conference proceedings; dementia; lipids; microglia; neuroinflammation; risk factor; therapeutics; vasculature.

PubMed Disclaimer

Conflict of interest statement

C. M. Kloske, M. C. Carrillo, S. Mahinrad, and C. E. Sexton are all full time employees of the Alzheimer's Association. M. Belloy has nothing to disclose. E. E. Blue was was funded by the National Institutes of Health/National Institute on Aging grant number R01AG059737 and is related to her work funded by grant number U01AG058589. Dr. Blue is a member of the Board of Directors for the International Genetic Epidemiology Society. G. R. Bowman holds equity in Decrypt Biomedicine. X. Chen has nothing to disclose. O. Chiba‐Falek is a co‐inventor of the related IP. Duke University filed patent applications for the technology developed in this study. CLAIRIgene has an exclusive, worldwide option agreement from Duke for the related patent portfolio for all fields of use. Dr. Chiba‐Falek is a Co‐Founder at CLAIRIgene, LLC. A. Davis has nothing to disclose. G. Di Paolo is a full‐time employee and shareholder of Denali Therapeutics Inc. F. Garretti has nothing to disclose. D. Gate has nothing to disclose. L. M. Golden has nothing to disclose. J. Heinecke has nothing to disclose. J.Herz is a cofounder of Reelin Therapeutics. Y. Huang has nothing to disclose. C. Iadecola has nothing to disclose. L. A. Johnson has nothing to disclose. T. Kanekiyo has nothing to disclose. C. Karch has nothing to disclose. A.Khvorova is a Co‐Founder of Atalanta. S. Koppes‐den Hertog has nothing to disclose. B. Lamb Co‐Founded of Monument Biosciences. P. E. Lawler has nothing to disclose. Y. Le Guen has nothing to disclose. A. Litvinchuk has nothing to disclose. C. Liu has nothing to disclose. E. Marcora has nothing to disclose. C. Marino has nothing to disclose. D. M. Michaelson has nothing to disclose. J. J. Miller has nothing to disclose. J. M. Morganti has nothing to disclose. P. S. Narayan has nothing to disclose. M. S. Naslavsky has nothing to disclose. M. Oosthoek has nothing to disclose. K. V. Ramachandran has nothing to disclose. A Ramakrishnan has nothing to disclose. A. Raulin has nothing to disclose. A. Robert has nothing to disclose. R. N. M. Saleh has nothing to disclose. N. Shah is an employee of Lexeo Therapeutics. F. Shue has nothing to disclose. I. J. Sible has nothing to disclose. A. Soranno has nothing to disclose. M. R. Strickland has nothing to disclose. J. TCW has nothing to disclose. M. Thierry has nothing to disclose. L. Tsai has nothing to disclose. R. A. Tuckey has nothing to disclose. J. D. Ulrich has nothing to disclose. R. van der Kant has nothing to disclose. N. Wang has nothing to disclose. C. L. Wellington has nothing to disclose. S. C. Weninger has nothing to disclose. H. N. Yassine has nothing to disclose. N. Zhao has nothing to disclose. G. Bu is the Editor‐in‐Chief of Molecular Neurodegeneration and a consultant for SciNeuro Pharmaceutical. A. M. Goate serves on the scientific advisory boards for Genentech and Muna Therapeutics. D. M. Holtzman is an inventor on a patent licensed by Washington University to NextCure on the therapeutic use of anti‐APOE antibodies. Pub. No. US 2022/0411485 A1 Pub date Dec 29, 2022. Title of patent: ANTI‐APOE ANTIBODIES. D.M.H. co‐founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid. Author disclosures are available in the supporting information.

References

1. Havel RJ, Kane JP, Kashyap ML. Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man. J Clin Invest. 1973;52:32‐38. doi:10.1172/JCI107171 - DOI - PMC - PubMed
1. Utermann G, Jaeschke M, Menzel J. Familial hyperlipoproteinemia type III: deficiency of a specific apolipoprotein (APO E‐III) in the very‐low‐density lipoproteins. FEBS Lett. 1975;56:352‐355. doi:10.1016/0014-5793(75)81125-2 - DOI - PubMed
1. Zannis VI, Breslow JL, Utermann G, et al. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res. 1982;23:911‐914. - PubMed
1. Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 2000;1:507‐537. doi:10.1146/annurev.genom.1.1.507 - DOI - PubMed
1. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467‐1467. doi:10.1212/WNL.43.8.1467 - DOI - PubMed

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Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

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Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference

Authors

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Abstract

Conflict of interest statement

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