Targeting Neuroplasticity, Cardiovascular, and Cognitive-Associated Genomic Variants in Familial Alzheimer’s Disease
Cargando...
Archivos
Fecha
2018-08
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
Título de la revista
ISSN de la revista
Título del volumen
Editor
SpringerLink
Resumen
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 APOE*E2 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 APOE*E2 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.
Descripción
Palabras clave
Alzheimer's disease, APOE*E2, Age of Onset, ASTN2, Genetic Isolate, PSEN1, Extreme phenotypes, SNTG1