variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.
|Title||variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Benedet AL, Yu L, Labbe A, Mathotaarachchi S, Pascoal TA, Shin M, Kang M-S, Gauthier S, Rouleau GA, Poirier J, Bennett DA, Rosa-Neto P|
|Corporate Authors||Alzheimer's Disease Neuroimaging Initiative|
|Date Published||2018 Feb|
Objective: To verify whether 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 [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 gene (rs4388808; = 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 ( = 0.003) and Aβ/p-tau ratio ( = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load ( = 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 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.
|Alternate Journal||Neurol Genet|
|PubMed Central ID||PMC5820598|
|Grant List||P30 AG010161 / AG / NIA NIH HHS / United States|