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CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem

OBJECTIVE: To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. METHODS: A candidate-gene approach tested the association between 5 genes (28 single nucleotide...

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Detalles Bibliográficos
Autores principales: Benedet, Andréa L., Yu, Lei, Labbe, Aurélie, Mathotaarachchi, Sulantha, Pascoal, Tharick A., Shin, Monica, Kang, Min-Su, Gauthier, Serge, Rouleau, Guy A., Poirier, Judes, Bennett, David A., Rosa-Neto, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820598/
https://www.ncbi.nlm.nih.gov/pubmed/29473050
http://dx.doi.org/10.1212/NXG.0000000000000216
Descripción
Sumario:OBJECTIVE: To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. METHODS: A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [(18)F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. RESULTS: Analysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ. CONCLUSIONS: Together, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.