Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.
PLoS Genet. 2013;9(8):e1003685. doi: 10.1371/journal.pgen.1003685. Epub 2013 Aug 22.
The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.
淀粉样斑块（Aβ42/Aβ40）和神经原纤维缠结（tau 和磷酸化 tau [ptau]）的主要成分是目前用于 AD 的主要诊断和预后性脑脊液（CSF）生物标志物。在这项研究中，我们对 Aβ42、tau 或 ptau 水平极高的个体进行了 APP、PSEN1、PSEN2、GRN、APOE 和 MAPT 基因的深度测序。发现了一个已知的致病性突变（PSEN1 p.A426P）、四个 AD 高危变异（APOE p.L46P、MAPT p.A152T、PSEN2 p.R62H 和 p.R71W）和九个新变异。令人惊讶的是，PSEN1 中的一个编码变异，p.E318G（rs17125721-G）与高 CSF tau（p = 9.2×10(-4))和 ptau（p = 1.8×10(-3))水平显著相关。APOE-ε4 等位基因携带者中观察到 p.E318G 变异与 Aβ 沉积的相关性。此外，我们发现，在一个大型病例对照系列（n = 5161）中，携带 APOE-ε4 且携带 p.E318G 变异的个体患 AD 的风险增加（OR = 10.7，95%CI = 4.7-24.6），与 APOE-ε4 纯合子（OR = 9.9，95%CI = 7.2.9-13.6）相似，而携带 p.E318G 变异的 APOE-ε4 携带者的风险是不携带 p.E318G 的个体的两倍（OR = 3.9，95%CI = 3.4-4.4）。在来自大型 LOAD 家族临床系列（n = 565）的 30 个（5.3%）家族中存在 p.E318G 变异，其在家族性 LOAD 中的频率（MAF = 2.5%）高于散发性 LOAD（MAF = 1.6%）（p = 0.02）。此外，我们发现，在至少携带一个 APOE-ε4 等位基因的情况下，p.E318G 与更多的 Aβ 斑块和更快的认知能力下降有关。我们证明，PSEN1，p.E318G 对 AD 易感性的影响在很大程度上取决于与 APOE-ε4 的相互作用，并通过 Aβ 沉积负担的增加来介导。
