Longitudinal Study of Lipids and APOE in the Development of AD and AD Pathology

脂质和 APOE 在 AD 发展和 AD 病理学中的纵向研究

• 批准号: 8325131
• 负责人: Michelle M Mielke
• 金额: $ 60.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325131
• 关键词: Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Atrophic; Baltimore; Biological Assay; Blood; Blood Vessels; Brain; Brain Pathology; Ceramides; Cholesterol; Cholesterol Esters; Clinical; Clinical Research; Cognition; Collection; Data; Dementia; Demographic Factors; Deposition; Development; Diabetes Mellitus; Diagnosis; Diet; Discipline; Disease; Elderly; Epidemiologic Studies; Epidemiology; Fasting; Fatty Acids; Funding; Future; Gangliosides; Genes; Genotype; Hippocampus (Brain); Homeostasis; Human; Hypertension; Image; Impaired cognition; Individual; Lesion; Life; Lipids; Lipoprotein Receptor; Literature; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Memory; Metabolism; NIH Program Announcements; Nerve Degeneration; Neurofibrillary Tangles; Normal Range; Omega-3 Fatty Acids; Participant; Pathogenesis; Pathology; Patients; Pattern; Performance; Peripheral; Persons; Phase; Physical activity; Plasma; Positron-Emission Tomography; Presenile Alzheimer Dementia; Prevention strategy; Research Personnel; Risk; Risk Factors; Role; Sample Size; Sampling; Scanning; Sphingolipids; Sterols; Symptoms; Testing; Time; Vascular Diseases; Visit; aged; aging brain; apolipoprotein E-4; base; cerebral atrophy; cohort; cost effective; disease diagnosis; follow-up; genetic risk factor; hippocampal atrophy; lifestyle factors; middle age; mild neurocognitive impairment; neuroimaging; neuropsychiatry; public health relevance; vascular factor; white matter

DESCRIPTION (provided by applicant): The E4 allele of the Apolipoprotein E (ApoE) gene is the strongest genetic risk factor for the onset of sporadic Alzheimer's disease (AD) identified to date. The roles by which ApoE influences amyloid-beta (A2) metabolism and non-A2-mediated mechanisms in AD pathogenesis, however, remain to be fully clarified. The literature, and our preliminary data, suggest that early alterations in peripheral lipids (sphingolipids, fatty acids, cholesterol and cholesterol esters) reflect brain functioning and pathology, and may interact with ApoE genotype in the development of AD pathogenesis, warranting human studies. Clinical and epidemiological studies of short duration, while important, will not contribute to our understanding of the earliest phases of AD pathogenesis because Alzheimer's pathology (A2 plaques and neurofibrillary tangles) begins decades before the emergence of symptoms and substantial neurodegeneration. Identifying factors years before the onset of AD that may modify the effects of ApoE4 in initiating and promoting AD pathology and the subsequent emergence of symptoms will uniquely contribute to the development of prevention strategies. Longitudinal studies of cognitively normal individuals with serial measures of Alzheimer's pathology in the living brain, as proposed here in the unique cohort of the Baltimore Longitudinal Study of Aging (BLSA), initiated in 1958, are necessary to understand the relationship between ApoE4 genotype, perturbations in peripheral lipids, their interaction, and later development of AD clinical symptoms and brain alterations. The BLSA is one of few human studies that could provide the unprecedented opportunity to systematically examine this relationship over a long follow-up. BLSA participants, cognitively normal at their first visit in the study (mean age: 63.4), have a mean follow-up of 14.3 years (SD = 6.5) and a maximum follow-up of 38.9 years. In the proposed study we will measure plasma lipid levels (sphingolipids, fatty acids, cholesterol and cholesterol esters) at three early visit in the BLSA study, roughly 5 years apart, for those aged 55 and over (n=1095), and at the last visit, as well as during the neuroimaging sub-study. The specific aims include examining the proposed peripheral lipids, changes in these lipids over a long follow-up, and their interaction with ApoE to predict: 1) decline in tests of memory; 2) incident MCI, all-cause dementia, and AD; 3) change in serial MRI measures of brain atrophy and white matter lesion burden over 10 years; and 4) amyloid-beta deposition on 11C-PIB PET scans. The lipids will be assayed using an already-developed targeted and quantitative lipidomic approach. PUBLIC HEALTH RELEVANCE: Many potent risk factors for Alzheimer's disease (AD), including hypertension and high cholesterol, are most detrimental in mid-life, presumably at the emergence of AD pathology, but have less of an effect on AD risk in late-life. Identifying factors in mid-life that may modify the effects of APOE E4 in initiating AD pathology, and the subsequent emergence of symptoms, will uniquely contribute to the development of prevention strategies. The overall aim of the proposed study is to examine, in the 50-year Baltimore Longitudinal Study of Aging, whether plasma lipids measured in mid-life (sphingolipids, gangliosides, fatty acids, cholesterol and cholesterol esters) modify the association between APOE and cognitive decline, clinical onset of mild cognitive impairment or AD, and neuroimaging measures of brain atrophy and brain pathology.

描述(由申请人提供)：载脂蛋白E(ApoE)基因的E4等位基因是迄今为止发现的导致散发性阿尔茨海默病(AD)发病的最强的遗传风险因素。然而，载脂蛋白E影响淀粉样β蛋白(A2)代谢的作用以及非A2介导的机制在AD发病中的作用仍未完全阐明。这些文献和我们的初步数据表明，外周脂肪(鞘磷脂、脂肪酸、胆固醇和胆固醇酯)的早期变化反映了大脑的功能和病理，并可能与ApoE基因在AD发病机制的发展中相互作用，这值得进行人类研究。短期的临床和流行病学研究虽然重要，但不会有助于我们了解AD发病的早期阶段，因为阿尔茨海默病的病理(A2斑块和神经原纤维缠结)在出现症状和实质性神经变性之前几十年就开始了。在阿尔茨海默病发病前几年确定可能改变载脂蛋白E4在启动和促进阿尔茨海默病病理和随后出现症状方面的影响的因素，将独特地有助于制定预防战略。在1958年开始的巴尔的摩老龄化纵向研究(BLSA)的独特队列中建议，对认知正常的人进行一系列阿尔茨海默氏病活脑病理指标的纵向研究，对于了解ApoE4基因、外周血脂扰动、它们之间的相互作用以及AD临床症状和脑变化的后来发展之间的关系是必要的。BLSA是为数不多的几项人类研究之一，它可以提供前所未有的机会，在长期的后续行动中系统地检查这种关系。BLSA参与者在研究中首次就诊时认知正常(平均年龄：63.4岁)，平均随访时间为14.3年(SD=6.5)，最长随访时间为38.9年。在拟议的研究中，我们将在BLSA研究的三个早期就诊时(大约相隔5年)、55岁及以上患者(n=1095)、最后一次就诊时以及神经成像子研究期间测量血脂水平(鞘磷脂、脂肪酸、胆固醇和胆固醇酯)。具体目标包括检查拟议的外周血脂，这些血脂在长期随访中的变化，以及它们与ApoE的相互作用，以预测：1)记忆测试的下降；2)发生MCI、全原因痴呆和AD；3)10年来脑萎缩和白质病变负担的系列MRI测量的变化；以及4)11C-PIB PET扫描上的淀粉样β沉积。这些脂质将使用已经开发的靶向和定量的脂质组学方法进行分析。 与公共健康相关：许多阿尔茨海默病(AD)的潜在危险因素，包括高血压和高胆固醇，在中年是最有害的，大概是在AD病理出现时，但在晚年对AD风险的影响较小。确定中年因素可能会改变APOE E4在启动AD病理过程中的影响，以及随后出现的症状，这将独特地有助于预防策略的制定。这项拟议研究的总体目标是，在为期50年的巴尔的摩老龄化纵向研究中，研究中年测得的血浆脂类(神经鞘糖脂、神经节苷脂、脂肪酸、胆固醇和胆固醇酯)是否改变了载脂蛋白E与认知功能下降、轻度认知障碍或AD的临床发病以及脑萎缩和脑病理的神经成像指标之间的关联。