Project 1: Early-Onset Alzheimers Disease: Imaging and Genetic Phenotypes

项目1：总结/摘要 大约5%的阿尔茨海默病（AD）患者在65岁之前出现症状， 不存在已知的常染色体显性突变。非家族性早发性AD（EO-AD）患者显示 执行功能、注意力、语言和视觉空间能力的缺陷更大，但相对较少 与晚发性AD（LO-AD）患者相比，非遗忘性和保留性 AD表型在EO疾病患者中更为常见。在EO患者中准确诊断AD是 由于非典型临床表现和与非AD痴呆重叠以及误诊， 即使在专家中心，发病率也很高。分子和神经退行性生物标志物可能有助于早期 和准确的诊断，但很少有研究讨论它们在EO疾病患者中的性能- LO-AD研究的结果可能无法推广到EO人群，因为退行性病变的差异 模式和参考范围。此外，EO-AD患者可能具有未被识别的易感性， 导致在如此年轻的年龄发病的因素。而载脂蛋白E等位基因强烈 与年轻的发病年龄相关，它只存在于约50%的EO患者中，这表明额外的 脆弱性的机制尚待发现。利用UCSF ADRC的优势， 招募和表征早发性AD患者，本研究将应用详细的临床表型， 多模式神经成像和新的遗传方法，以优化早期诊断， EO-AD中的脆弱性机制。我们将评估100例轻度受损（CDR 0.5-1）早发性 （估计发病年龄≤65岁）从临床核心招募的患者。所有患者均符合NIA-AA标准， MCI或可能的AD，并基于阳性淀粉样蛋白（florbetapir）PET证明AD病理学证据 扫描.来自100名匹配的正常对照（NC）和75名非AD痴呆患者的比较数据将在 通过临床和成像核心获取。目的1将测试（1）CSF和（2）的诊断性能 基于海马与基于皮质的MRI生物标志物区分EO-AD与NC和非AD 痴呆目的2将建立在初步数据的基础上，这些数据表明ApoE 4改变了EO-AD的表型， 假设ApoE 4携带者将显示更大的记忆障碍和海马萎缩， 与E4非携带者相比。一个产生假设的目标3将应用新的遗传工具来研究 EO-AD的易感因素，假设：（1）ApoE 4阳性和E4阴性患者将显示 外周血中的差异基因表达模式，反映了不同生物学途径的参与; 和（2）通过使用基因芯片筛选EO-AD患者，该基因芯片包括约250，000个罕见的蛋白质改变基因， 标志物，我们将确定新的风险变异的基因参与AD致病途径。总体而言，这 该项目将有助于早期和准确诊断EO-AD，并将进一步了解 与老年前期疾病发病相关的易感因素。

PROJECT 1: SUMMARY/ABSTRACT Approximately 5% of patients of with Alzheimer's Disease (AD) develop symptoms before age 65 in the absence of a known autosomal dominant mutation. Patients with non-familial early-onset AD (EO-AD) show greater deficits in executive function, attention, language and visuospatial abilities and relatively spared episodic memory compared to patients with late-onset AD (LO-AD). Non-amnestic and hippocampal-sparing AD phenotypes are far more common in patients with EO disease. Accurately diagnosing AD in EO patients is challenging due to the atypical clinical presentations and overlap with non-AD dementia, and misdiagnosis rates are high even at expert centers. Molecular and neurodegenerative biomarkers are likely to facilitate early and accurate diagnosis, but few studies have addressed their performance in patients with EO disease - results from LO-AD studies may not generalize to EO populations because of differences in degenerative patterns and reference ranges. Furthermore, patients with EO-AD may harbor unrecognized susceptibility factors that lead to disease onset at such a young age. While the apolipoprotein E ϵ4 allele is strongly correlated with young age-of-onset, it is present in only ~50% of EO patients, suggesting that additional mechanisms of vulnerability have yet to be discovered. Leveraging on the strength of the UCSF ADRC in recruiting and characterizing patients with early-onset AD, this study will apply detailed clinical phenotyping, multi-modal neuroimaging and novel genetic approaches to optimize early-stage diagnosis and to elucidate mechanisms of vulnerability in EO-AD. We will evaluate 100 mildly impaired (CDR 0.5-1) early-onset (estimated age of onset ≤65) patients recruited from the Clinical core. All patients will meet NIA-AA criteria for MCI or probable AD and demonstrate evidence of AD pathology based on a positive amyloid (florbetapir) PET scan. Comparative data from 100 matched normal controls (NC) and 75 non-AD dementia patients will be acquired via the Clinical and Imaging cores. Aim 1 will test the diagnostic performance of (1) CSF and (2) hippocampal versus cortically-based MRI biomarkers in distinguishing EO-AD from NC and non-AD dementia. Aim 2 will build on preliminary data suggesting that ApoE4 modifies the phenotype of EO-AD, testing the hypothesis that ApoE4 carriers will show greater memory impairment and hippocampal atrophy and lower amyloid compared to E4 non-carriers. A hypothesis-generating Aim 3 will apply novel genetic tools to study vulnerability factors in EO-AD, hypothesizing that: (1) ApoE4-positive and E4-negative patients will show differential gene expression patterns in peripheral blood, reflecting involvement of distinct biological pathways; and (2) by screening EO-AD patients with a gene chip that includes ~250,000 rare, protein-altering genetic markers, we will identify novel risk variants in genes implicated in AD pathogenic pathways. Overall, this project will facilitate the early and accurate diagnosis of EO-AD, and will further our understanding of susceptibility factors associated with pre-senile disease onset.