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
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.
Neurol Genet. 2018 Jan 30;4(1):e216. doi: 10.1212/NXG.0000000000000216. eCollection 2018 Feb.
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.
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.
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.
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.
利用来自2个独立队列的体内和死后数据，验证多态性是否与临床阿尔茨海默病全谱中的β淀粉样蛋白（Aβ）病理相关。
采用候选基因方法，测试了5个基因（28个单核苷酸多态性）与338名阿尔茨海默病神经影像学倡议参与者体内通过全局[F]氟代贝他吡正电子发射断层扫描标准化摄取值比率（SUVR）测量的Aβ负荷之间的关联。然后在同一队列中使用血浆Aβ、脑脊液Aβ和Aβ/磷酸化tau（Aβ/p-tau）比率对显著结果进行测试。这种显著关联也推广到拉什宗教团体研究/记忆与衰老项目队列中的死后Aβ负荷测量。此外，在两个队列的分析中均将整体认知作为一种表型。
对Aβ正电子发射断层扫描的分析在基因中鉴定出一个变体（rs4388808；P = 0.0006），其中次要等位基因（MA）携带者的全局SUVR较低。基于体素的分析显示，该变体与额叶、颞下回和后扣带回皮质中较低的Aβ负荷相关。MA携带者的脑脊液Aβ（P = 0.003）和Aβ/p-tau比率也较高（P = 0.02），但与血浆Aβ水平无关。在死后大脑中，MA携带者的Aβ负荷较低（P = 0.03）。MA携带者的整体认知较高，发现这是由Aβ介导的。
总之，这些发现表明基因多态性与Aβ病理之间存在关联，提示rs4388808的MA具有保护作用。尽管基因影响脑Aβ有多种可能性，但这种基因变异作为保护因素的生物学机制值得进一步研究。
