variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.

Title variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.
Publication TypeJournal Article
Year of Publication2018
AuthorsBenedet 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 AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalNeurol Genet
Date Published2018 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 JournalNeurol Genet
PubMed ID29473050
PubMed Central IDPMC5820598
Grant ListP30 AG010161 / AG / NIA NIH HHS / United States