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

项目1：摘要/摘要 大约5%的阿尔茨海默病(AD)患者在65岁之前出现症状 没有已知的常染色体显性突变。非家族性早发性AD(EO-AD)患者表现 在执行功能、注意力、语言和视觉空间能力方面存在较大缺陷，相对较少 与晚发性阿尔茨海默病(LO-AD)患者的情景记忆比较。非遗忘性和保留海马区 AD表型在EO病患者中更为常见。准确诊断EO患者的AD 由于不典型的临床表现和与非AD痴呆重叠，以及误诊，具有挑战性 即使在专家中心，这一比例也很高。分子和神经退行性生物标记物可能有助于早期 和准确的诊断，但很少有研究讨论它们在EO疾病患者中的表现- Lo-AD研究的结果可能不会推广到EO人群，因为退行性变的差异 图案和参考范围。此外，EO-AD患者可能存在无法识别的易感性 导致疾病在如此年轻时发病的因素。而载脂蛋白E？4等位基因则强烈 与年轻发病年龄相关，只有~50%的EO患者存在这种情况，这表明额外的 脆弱性的机制还有待发现。利用加州大学旧金山分校ADRC的实力 招募和表征早发性AD患者，这项研究将应用详细的临床表型， 多模式神经成像和新的遗传学方法优化早期诊断和阐明 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D65)从临床核心招募的患者。所有患者都将符合NIA-AA标准 MCI或可能的AD，并基于阳性的淀粉样蛋白(Florbetapir)PET证明AD的病理证据 扫描。来自100名匹配的正常对照组(NC)和75名非AD痴呆患者的比较数据将被 通过临床和成像核心获得。目标1将测试(1)脑脊液和(2)脑脊液的诊断性能 海马区与皮质MRI生物标志物在鉴别EO-AD与NC和非AD中的作用 痴呆症。目标2将建立在初步数据的基础上，表明ApoE4修改了EO-AD的表型，测试 假设载脂蛋白E4携带者将表现出更大的记忆障碍和海马区萎缩和更低的 淀粉样蛋白与E4非携带者的比较。假设生成目标3将应用新的遗传工具来研究 EO-AD的易感性因素，假设：(1)ApoE4阳性和E4阴性的患者将表现出 外周血中基因表达模式的差异，反映了不同的生物途径的参与； 以及(2)通过使用基因芯片筛选EO-AD患者，该基因芯片包含约250,000个罕见的、改变蛋白质的基因 标记，我们将识别AD致病途径中涉及的基因中的新的风险变异。总体而言，这 该项目将有助于EO-AD的早期和准确诊断，并将加深我们对 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 ¿4 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 d65) 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.