Send to

Choose Destination
Neurol Genet. 2018 Jan 30;4(1):e216. doi: 10.1212/NXG.0000000000000216. eCollection 2018 Feb.

CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.

Author information

Translational Neuroimaging Laboratory (A.L.B., S.M., T.A.P., M.S., M.-S.K., P.R.-N.), and Alzheimer's Disease Research Unit (S.G., P.R.-N.), McGill University Research Centre for Studies in Aging, Montreal, Canada; CAPES Foundation (A.L.B.), Ministry of Education of Brazil, Brasília, Brazil; Rush Alzheimer's Disease Center (L.Y., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Decision Sciences (A.L.), HEC Montreal, Montreal, Canada; Department of Epidemiology (A.L.), Biostatistics & Occupational Health, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery (G.A.R., J.P., P.R.-N.), Douglas Hospital Research Centre (J.P., P.R.-N.), and Department of Psychiatry (J.P.), McGill University, Montreal, Canada; and Montreal Neurological Institute (G.A.R., P.R.-N.), Canada.



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.


A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]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.


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.


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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center