Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, United States of America.
PLoS One. 2012;7(8):e40527. doi: 10.1371/journal.pone.0040527. Epub 2012 Aug 21.
Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed.
阿尔茨海默病（AD）是老年人痴呆的主要原因。由于这种疾病的病理变化可能在认知障碍出现前几十年就开始了，因此确定 AD 病理级联反应中的最早事件对这种疾病的诊断和治疗都具有重要意义。我们之前曾报道过，与经尸检证实的健康对照组大脑相比，LR11（或 SorLA）的表达在 AD 大脑以及轻度认知障碍（MCI）的一部分人群中明显降低，MCI 是 AD 的一个前驱临床阶段。最近对 LR11 基因 SORL1 的研究表明，SORL1 单核苷酸多态性（SNP）与 AD 风险之间的关联可能并不普遍。因此，我们试图在仅根据临床标准选择的人群中证实我们之前的发现，就像大多数遗传研究一样。定量免疫组织化学用于测量来自宗教秩序研究的 43 例病例的 LR11 表达，这些病例是根据生前最终临床诊断为 MCI、轻度/中度 AD 或无认知障碍（NCI）选择的。LR11 表达在所有三个诊断组中均高度可变，且组间无显著差异。使用所有病例中观察到的 LR11 表达的最低三分位数作为阈值，确定低 LR11 病例。与之前的报告相反，AD 病例中仅发现低 LR11 表达的病例占 29%。MCI 和 NCI 病例也有相似比例的低 LR11 表达。无论诊断组如何，大多数病例都存在 AD 相关病变，尽管我们没有发现 LR11 水平与病理变量之间存在关联。这些发现表明，LR11 表达与 AD 发展之间的关系可能比最初想象的更为复杂。
