Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease.


Journal

Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449

Informations de publication

Date de publication:
05 Jan 2024
Historique:
revised: 06 12 2023
received: 28 10 2023
accepted: 09 12 2023
medline: 5 1 2024
pubmed: 5 1 2024
entrez: 5 1 2024
Statut: aheadofprint

Résumé

Alzheimer's disease (AD) is the most common neurodegenerative disorder and one of the leading causes of disability worldwide. The apolipoprotein E4 gene (APOE4) is the strongest genetic risk factor for AD. In 2023, the APOE4 National Institute on Aging/Alzheimer's Disease Sequencing Project working group came together to gather data and discuss the question of whether to reduce or increase APOE4 as a therapeutic intervention for AD. It was the unanimous consensus that cumulative data from multiple studies in humans and animal models support that lowering APOE4 should be a target for therapeutic approaches for APOE4 carriers. ANN NEUROL 2024.

Identifiants

pubmed: 38180638
doi: 10.1002/ana.26864
doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Références

Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high avidity binding to ß-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:1977-1981.
Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid ß peptide: isoform specific-effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:8098-8102.
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;261:921-923.
Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer's disease: progress to date and the path forward. Neuron 2019;101:820-838.
Choi KY, Lee JJ, Gunasekaran TI, et al. APOE promoter polymorphism-219T/G is an effect modifier of the influence of APOE epsilon4 on Alzheimer's disease risk in a multiracial sample. J Clin Med 2019;8:1236.
Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele decreases risk of late onset Alzhimer disease. Nature Genet 1994;7:180-184.
Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease meta analysis consortium. JAMA 1997;278:1349-1356.
Graff-Radford NR, Green RC, Go RC, et al. Association between apolipoprotein E genotype and Alzheimer disease in African American subjects. Arch Neurol 2002;59:594-600.
Tang MX, Stern Y, Marder K, et al. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, Whites, and Hispanics. JAMA 1998;279:751-755.
Rajabli F, Feliciano BE, Celis K, et al. Ancestral origin of ApoE epsilon4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet 2018;14:e1007791.
Blue EE, Horimoto A, Mukherjee S, et al. Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics. Alzheimers Dement 2019;15:1524-1532.
Naslavsky MS, Suemoto CK, Brito LA, et al. Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample. Mol Psychiatry 2022;27:4800-4808.
Griswold AJ, Celis K, Bussies PL, et al. Increased APOE epsilon4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds. Alzheimers Dement 2021;17:1179-1188.
Nuytemans K, Lipkin Vasquez M, Wang L, et al. Identifying differential regulatory control of APOE varepsilon4 on African versus European haplotypes as potential therapeutic targets. Alzheimers Dement 2022;18:1930-1942.
Celis K, Moreno M, Rajabli F, et al. Ancestry-related differences in chromatin accessibility and gene expression of APOE epsilon4 are associated with Alzheimer's disease risk. Alzheimers Dement 2023;19:3902-3915.
Rajabli F, Beecham GW, Hendrie HC, et al. A locus at 19q13.31 significantly reduces the ApoE epsilon4 risk for Alzheimer's disease in African ancestry. PLoS Genet 2022;18:e1009977.
Chemparathy A, Guen YL, Chen S, et al. APOE loss-of-function variants: compatible with longevity and associated with resistance to Alzheimer's disease pathology. Neuron 2023; in press.
Cruchaga C, Western D, Timsina J, et al. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease. Res Sq 2023;rs.3.rs-2814616.
Tcw J, Qian L, Pipalia NH, et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell 2022;185:2213-2233.e25.
Stanton AE, Bubnys A, Agbas E, et al. Engineered 3D immuno-glial-neurovascular human brain model. bioRxiv 2023.
Blanchard JW, Akay LA, Davila-Velderrain J, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 2022;611:769-779.
Victor MB, Leary N, Luna X, et al. Lipid accumulation induced by APOE4 impairs microglial surveillance of neuronal-network activity. Cell Stem Cell 2022;29:1197-1212.e8.
Wang C, Najm R, Xu Q, et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat Med 2018;24:647-657.
Blanchard JW, Bula M, Davila-Velderrain J, et al. Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat Med 2020;26:952-963.
Sunderland T, Mirza N, Putnam KT, et al. Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biol Psychiatry 2004;56:670-676.
Reiman EM, Chen K, Liu X, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A 2009;106:6820-6825.
Morris JC, Roe CM, Xiong C, et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 2010;67:122-131.
Castellano JM, Kim J, Stewart FR, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 2011;3:89ra57.
Holtzman DM, Bales KR, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2000;97:2892-2897.
Holtzman DM, Fagan AM, Mackey B, et al. ApoE facilitates neuritic and cerebrovascular plaque formation in the APPsw mouse model of Alzheimer's disease. Ann Neurol 2000;47:739-747.
Youmans KL, Tai LM, Nwabuisi-Heath E, et al. APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 2012;287:41774-41786.
Pankiewicz JE, Guridi M, Kim J, et al. Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun 2014;2:75.
Kim J, Jiang H, Park S, et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci 2011;31:18007-18012.
Bien-Ly N, Gillespie AK, Walker D, et al. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci 2012;32:4803-4811.
Huynh TV, Liao F, Francis CM, et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 2017;96:1013-1023.e4.
Liu CC, Zhao N, Fu Y, et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 2017;96:1024-1032.e3.
Mahan TE, Wang C, Bao X, et al. Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener 2022;17:13.
Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995;16:271-278. discussion 278-84.
Steward A, Biel D, Dewenter A, et al. ApoE4 and connectivity-mediated spreading of tau pathology at lower amyloid levels. JAMA Neurol 2023;80:1295-1306.
Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017;549:523-527.
Litvinchuk A, Huynh TV, Shi Y, et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann Neurol 2021;89:952-966.
Wang C, Xiong M, Gratuze M, et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 2021;109:1657-1674.e7.
Koutsodendris N, Blumenfeld J, Agrawal A, et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 2023;3:275-296.
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A 2010;107:12011-12016.
Xian X, Pohlkamp T, Durakoglugil MS, et al. Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease. Elife 2018;7:e40048.
Wintersteiner O, Abramson HA. The isoelectric point of insulin: electrical properties of adsorbed and crystalline insulin. J Biol Chem 1932;99:741-753.
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;25:1680-1683.
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;9:11.
Le Guen Y, Belloy ME, Grenier-Boley B, et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol 2022;79:652-663.
Chen Y, Song S, Parhizkar S, et al. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell 2023;S0092-8674(23)01315-6.
Nelson MR, Liu P, Agrawal A, et al. The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 2023;26:2104-2121.
Lee JH, Yang DS, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Abeta in neurons, yielding senile plaques. Nat Neurosci 2022;25:688-701.
Im E, Jiang Y, Stavrides PH, et al. Lysosomal dysfunction in down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF. Sci Adv 2023;9:eadg1925.
Pohlkamp T, Xian X, Wong CH, et al. NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load. Elife 2021;10:e72034.
Lee WP. Suppression of vacuolar-type ATPase and induction of endoplasmic reticulum stress by proton pump inhibitors. J Chin Med Assoc 2022;85:915-921.
Northuis C, Bell E, Lutsey P, et al. Cumulative use of proton pump inhibitors and risk of dementia: the atherosclerosis risk in communities study. Neurology 2023;101:e1771-e1778.
Dean DC 3rd, Jerskey BA, Chen K, et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol 2014;71(1):11-22.
Remer J, Dean DC 3rd, Chen K, et al. Longitudinal white matter and cognitive development in pediatric carriers of the apolipoprotein epsilon4 allele. Neuroimage 2020;222:117243.
Piers RJ. Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan. Neural Regen Res 2018;13:1309-1312.
Knickmeyer RC, Wang J, Zhu H, et al. Common variants in psychiatric risk genes predict brain structure at birth. Cereb Cortex 2014;24:1230-1246.
Meyer K, Feldman HM, Lu T, et al. REST and neural gene network dysregulation in iPSC models of Alzheimer's disease. Cell Rep 2019;26:1112-1127.e9.
Rajabli F, Seixas AA, Akgun B, et al. African ancestry APOE e4 non-carriers with higher educational attainment are resilient to Alzheimer disease pathology-specific blood biomarker pTau181. medRxiv 2023.
Pletnikova O, Rudow GL, Hyde TM, et al. Alzheimer lesions in the autopsied brains of people 30 to 50 years of age. Cogn Behav Neurol 2015;28:144-152.
Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Associations of Alzheimer disease-protective APOE variants with age-related macular degeneration. JAMA Ophthalmol 2023;141:13-21.
Fagan AM, Watson M, Parsadanian M, et al. Human and murine apoE markedly influence ab metabolism both prior and subsequent to plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis 2002;9:305-318.
Reiman EM, Arboleda-Velasquez JF, Quiroz YT, et al. Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun 2020;11:667.
Panitch R, Hu J, Chung J, et al. Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE epsilon2 protective effect in Alzheimer disease. Mol Psychiatry 2021;26:6054-6064.
Jun GR, You Y, Zhu C, et al. Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE varepsilon2 for Alzheimer's disease. Alzheimers Dement 2022;18:2042-2054.
Jackson RJ, Keiser MS, Meltzer JC, et al. APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. bioRxiv 2023.
Zhao L, Gottesdiener AJ, Parmar M, et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging 2016;44:159-172.
Rosenberg JB, Kaplitt MG, De BP, et al. 10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer's disease. Hum Gene Ther Clin Dev 2018;29:24-47.
Nagata T, Dwyer CA, Yoshida-Tanaka K, et al. Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS. Nat Biotechnol 2021;39:1529-1536.
Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: structural insights and links to Alzheimer disease pathogenesis. Neuron 2021;109:205-221.

Auteurs

Jeffery M Vance (JM)

John T. McDonald Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.

Lindsay A Farrer (LA)

Departments of Medicine (Biomedical Genetics), Neurology and Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Departments of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA, USA.

Yadong Huang (Y)

Department of Neurology, Gladstone Center for Translational Advancement, Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA, USA.

Carlos Cruchaga (C)

Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.

Bradley T Hyman (BT)

Alzheimer Research Unit, Department of Neurology, The Massachusetts General Hospital Institute for Neurodegenerative Disease, Harvard Medical School, Boston, MA, USA.

Margaret A Pericak-Vance (MA)

John T. McDonald Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.

Alison M Goate (AM)

Departments of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer's disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Michael D Greicius (MD)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Anthony J Griswold (AJ)

John P. Hussman Institute for Human Genomics, The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

Jonathan L Haines (JL)

Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.

Julia Tcw (J)

Departments of Pharmacology, Physiology & Biophysics, Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Bioinformatics Program, Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA.

Gerard D Schellenberg (GD)

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Li-Huei Tsai (LH)

Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.

Joachim Herz (J)

Departments of Molecular Genetics, Neuroscience, Neurology, Center for Translational Neurodegeneration Research, UT Southwestern, Dallas, TX, USA.

David M Holtzman (DM)

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.

Classifications MeSH