Integrative translational discovery of vascular risk factors in aging and dementia

 描述(申请人提供)：阿尔茨海默病(AD)是一种进行性神经退行性疾病，其特征是淀粉样蛋白(Aβ，Aβ)以老年斑的形式沉积在脑实质，在脑血管系统以脑淀粉样血管病的形式沉积。CAA也是老年人颅内出血的主要原因。流行病学研究表明，血管系统的紊乱在AD和CAA的发病机制中均有作用。另外，载脂蛋白E基因的ε4等位基因是阿尔茨海默病和慢性再生障碍性贫血最强的遗传危险因素。载脂蛋白E4会加剧A-β在大脑中的积聚，导致血脑屏障的破坏和小血管的减少。虽然APOE4携带者总体上患AD的风险更高，但APOE4对女性的影响明显强于男性。我们的初步结果一致地表明，在女性中，载脂蛋白4与CAA严重程度的遗传相关性比男性更强。虽然女性患AD的风险更高，但我们发现男性在AD中比女性有更严重的CAA。这些数据表明，在CAA和AD的发展过程中存在性别特异性的、载脂蛋白E依赖和独立的分子通路。在这项提案中，我们的目标是明确性别和载脂蛋白E亚型如何不同地影响AD和CAA的风险，并确定在衰老和AD中参与脑血管病理的新基因和新途径。我们将使用跨学科、基于系统的方法，利用现有的神经病理学、基因组/表观基因组和神经成像领域的新数据，在表型丰富的大型尸检脑部收集和纵向跟踪的老年队列中产生新的数据，梅奥老年诊所研究(MCSA)。我们全面的假说驱动和假说生成研究将为AD患者CAA和其他脑血管病变的分子机制提供新的见解。我们的具体目标如下：目的1.明确性别和载脂蛋白E亚型对CAA和实质淀粉样斑块的病理分布和严重程度的影响；目的2.识别促进CAA和AD发展的新途径；目的3.发现新途径对衰老和痴呆中血管风险的影响；目的4.研究载脂蛋白E亚型和雌激素影响脑Aβ清除和CAA和淀粉样斑块形成的分子机制。总而言之，这些研究有望揭示AD/CAA的载脂蛋白E和性别影响的潜在机制，并发现新的基因和途径，将成为候选的诊断和治疗靶点。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) in the brain parenchyma as senile plaques and in the cerebrovasculature as cerebral amyloid angiopathy (CAA). CAA is also a major cause of intracranial hemorrhage in the elderly. Epidemiological studies indicate that disturbance of the vascular system contributes to the pathogenesis of both AD and CAA. In addition, the ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for both AD and CAA. ApoE4 exacerbates Aβ accumulation in the brain, causes blood-brain barrier breakdown and reduction of small vessels. While APOE4 carriers have a higher risk for AD in general, APOE4 effect is significantly stronger in females compared to males. Consistently, our preliminary results indicate that APOE4 has a stronger genetic association with CAA severity in females than males. Although females have a higher risk for AD, we found that males have more severe CAA than females in AD. These data suggest the presence of sex-specific, and both apoE-dependent and independent molecular pathways in the development of CAA and AD. In this proposal, we aim to define how sex and apoE isoforms differentially affect the risk for AD and CAA, and to identify novel genes and pathways that contribute to cerebrovascular pathology in aging and AD. We will use interdisciplinary, systems-based approaches by leveraging existing and generating new data in neuropathology, genome/epigenome, and neuroimaging fields in richly phenotyped, large autopsy brain collections and the longitudinally followed, elderly cohort, Mayo Clinic Study of Aging (MCSA). Our comprehensive hypothesis-driven and hypothesis-generating studies will provide novel insights into the molecular mechanisms underlying CAA and other cerebrovascular pathologies in AD. Our specific aims are as follows: Aim 1. Define the effects of sex and apoE isoforms on the pathological distribution and severity of CAA and parenchymal amyloid plaques; Aim 2. Identify novel pathways that contribute to the development of CAA and AD; Aim 3. Discover the impact of novel pathways on vascular risk in aging and dementia; Aim 4. Investigate the molecular mechanisms mediating the impact of apoE isoforms and estrogen on brain Aβ clearance and the formation of CAA and amyloid plaques. Collectively, these studies are expected to both uncover mechanisms underlying apoE and sex effects for AD/CAA and discover novel genes and pathways that will be candidate diagnostic and therapeutic targets.