Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease

Background: The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer’s disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. Methods: We recruited 78 individuals with AD from...

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Autores:: Vélez, Jorge I.
Lopera, Francisco
Creagh, Penelope K.
Piñeros, Laura B.
Das, Debjani
Cervantes-Henríquez, Martha L.
Acosta-López, Johan E.
Isaza – Ruget, Mario A.
Espinosa, Lady G.
Easteal, Simon
Quintero, Gustavo A.
Tamar Silva, Claudia
Mastronardi, Claudio A.
Arcos-Burgos, Mauricio

Tipo de recurso:

Fecha de publicación:: 2018

Institución:: Universidad Simón Bolívar

Repositorio:: Repositorio Digital USB

Idioma:: eng

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dc.title.eng.fl_str_mv	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
title	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
spellingShingle	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease Alzheimer's disease APOE*E2 Age of Onset ASTN2 Genetic Isolate PSEN1 Extreme phenotypes SNTG1
title_short	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
title_full	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
title_fullStr	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
title_full_unstemmed	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
title_sort	Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
dc.creator.fl_str_mv	Vélez, Jorge I. Lopera, Francisco Creagh, Penelope K. Piñeros, Laura B. Das, Debjani Cervantes-Henríquez, Martha L. Acosta-López, Johan E. Isaza – Ruget, Mario A. Espinosa, Lady G. Easteal, Simon Quintero, Gustavo A. Tamar Silva, Claudia Mastronardi, Claudio A. Arcos-Burgos, Mauricio
dc.contributor.author.none.fl_str_mv	Vélez, Jorge I. Lopera, Francisco Creagh, Penelope K. Piñeros, Laura B. Das, Debjani Cervantes-Henríquez, Martha L. Acosta-López, Johan E. Isaza – Ruget, Mario A. Espinosa, Lady G. Easteal, Simon Quintero, Gustavo A. Tamar Silva, Claudia Mastronardi, Claudio A. Arcos-Burgos, Mauricio
dc.subject.eng.fl_str_mv	Alzheimer's disease APOE*E2 Age of Onset ASTN2 Genetic Isolate PSEN1 Extreme phenotypes SNTG1
topic	Alzheimer's disease APOE*E2 Age of Onset ASTN2 Genetic Isolate PSEN1 Extreme phenotypes SNTG1
description	Background: The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer’s disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. Methods: We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 30s to the late 70s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. Results: We identified two key epistatic interactions between the APOEE2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~8 years (95%CI: 3.2-12.7, P=1.83x10-3) and ~7.6 years (95%CI: 3.3-11.8, P = 8.69x10-4), respectively, and validated our previous finding indicating that APOEE2 delays AOO of AD in PSEN1 E280 mutation carriers. Discussion: This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.
publishDate	2018
dc.date.accessioned.none.fl_str_mv	2018-09-06T13:59:18Z
dc.date.available.none.fl_str_mv	2018-09-06T13:59:18Z
dc.date.issued.none.fl_str_mv	2018-08
dc.type.eng.fl_str_mv	article
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dc.identifier.issn.none.fl_str_mv	591182
dc.identifier.uri.none.fl_str_mv	http://hdl.handle.net/20.500.12442/2272
identifier_str_mv	591182
url	http://hdl.handle.net/20.500.12442/2272
dc.language.iso.eng.fl_str_mv	eng
language	eng
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dc.rights.license.spa.fl_str_mv	Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional
rights_invalid_str_mv	Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacional http://purl.org/coar/access_right/c_abf2
dc.publisher.eng.fl_str_mv	SpringerLink
dc.source.eng.fl_str_mv	Molecular Neurobiology Vol. 55, No.12035 (2018)
institution	Universidad Simón Bolívar
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spelling	Licencia de Creative Commons Reconocimiento-NoComercial-CompartirIgual 4.0 Internacionalhttp://purl.org/coar/access_right/c_abf2Vélez, Jorge I.83044e45-79cc-4eec-a9cc-72bf4514e76b-1Lopera, Francisco4a86ad59-fb7c-4ff9-8b91-2eec6406d886-1Creagh, Penelope K.71be7878-379b-4c35-bbd0-c4fbfa7cdde8-1Piñeros, Laura B.d2daa79f-ac46-4fe4-824d-3cd4dc70bbf2-1Das, Debjani183c6cd5-41ca-42ef-906b-007f0a982667-1Cervantes-Henríquez, Martha L.fb444be3-6d82-40aa-8a3c-75f422f8ec66-1Acosta-López, Johan E.b7a16ff4-ce8a-419c-a6ba-597013d207ed-1Isaza – Ruget, Mario A.77aaf152-7637-4361-a85e-f73dabaa0ff6-1Espinosa, Lady G.a6329e9c-3fbf-4476-a358-24bd9bb599d7-1Easteal, Simon8b0a5f8e-583d-4bc3-91d3-012b7ae80811-1Quintero, Gustavo A.a18f84ac-9fdd-4382-86f7-071e354b1b2e-1Tamar Silva, Claudia6c125055-e645-441c-a419-ec00b19745c4-1Mastronardi, Claudio A.55aa2248-59ef-49ea-9101-21682e3932a0-1Arcos-Burgos, Mauriciob0eeb625-a6f6-4508-8925-309b5f765a14-12018-09-06T13:59:18Z2018-09-06T13:59:18Z2018-08591182http://hdl.handle.net/20.500.12442/2272Background: The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer’s disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. Methods: We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 30s to the late 70s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. Results: We identified two key epistatic interactions between the APOEE2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~8 years (95%CI: 3.2-12.7, P=1.83x10-3) and ~7.6 years (95%CI: 3.3-11.8, P = 8.69x10-4), respectively, and validated our previous finding indicating that APOEE2 delays AOO of AD in PSEN1 E280 mutation carriers. Discussion: This new evidence involving APOEE2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.engSpringerLinkMolecular NeurobiologyVol. 55, No.12035 (2018)Alzheimer's diseaseAPOEE2Age of OnsetASTN2Genetic IsolatePSEN1Extreme phenotypesSNTG1Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Diseasearticlehttp://purl.org/coar/resource_type/c_6501Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimer's & Dementia. 2007;3(3):186-91.Arcos-Burgos M, Muenke M. Genetics of population isolates. Clinical Genetics. 2002;61(4):233-47.Acosta-Baena N, Sepulveda-Falla D, Lopera-Gomez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011;10(3):213-20.Lopera F, Ardilla A, Martinez A, Madrigal L, Arango-Viana JC, Lemere CA, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. Jama. 1997;277(10):793-9.Bravo ML, Valenzuela CY, Arcos-Burgos OM. Polymorphisms and phyletic relationships of the Paisa community from Antioquia (Colombia). Gene Geogr. 1996;10(1):11-7.Londono AC, Castellanos FX, Arbelaez A, Ruiz A, Aguirre-Acevedo DC, Richardson AM, et al. An 1H-MRS framework predicts the onset of Alzheimer's disease symptoms in PSEN1 mutation carriers. Alzheimers Dement. 2014;10(5):552-61.Velez JI, Chandrasekharappa SC, Henao E, Martinez AF, Harper U, Jones M, et al. Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease. Mol Psychiatry. 2013;18(5):568-75.Velez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A, et al. APOEE2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Molecular psychiatry. 2016;21(7):916-24.Velez JI, Rivera D, Mastronardi CA, Patel HR, Tobon C, Villegas A, et al. A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. Neural Plast. 2016;2016:9760314.Velez JI, Lopera F, Patel HR, Johar AS, Cai Y, Rivera D, et al. Mutations modifying sporadic Alzheimer's disease age of onset. 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