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: 8502599
• 负责人: Michelle M Mielke
• 金额: $ 45.83万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502599
• 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 cognitive 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（由申请方提供）：载脂蛋白E（ApoE）基因的E4等位基因是迄今为止发现的散发性阿尔茨海默病（AD）发病的最强遗传风险因素。然而，ApoE影响淀粉样蛋白β（A2）代谢和非A2介导的机制在AD发病机制中的作用仍有待充分阐明。文献和我们的初步数据表明，外周脂质（鞘脂、脂肪酸、胆固醇和胆固醇酯）的早期改变反映了脑功能和病理学，并可能与AD发病机制发展中的ApoE基因型相互作用，从而促进了人类研究。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发病机制的最早阶段，因为阿尔茨海默病的病理学（A2斑块和神经元缠结）在症状和实质性神经变性出现之前几十年就开始了。在AD发病前数年确定可能改变ApoE 4在启动和促进AD病理学和随后出现症状中的作用的因素，将独特地有助于预防策略的发展。认知正常个体的纵向研究，一系列措施阿尔茨海默氏病的病理学在活脑中，这里提出的独特队列的巴尔的摩纵向研究老化（BLSA），在1958年开始，是必要的，以了解之间的关系ApoE 4基因型，外周脂质的扰动，它们的相互作用，以及后来的发展AD临床症状和大脑的改变。BLSA是为数不多的人类研究之一，可以提供前所未有的机会，在长期随访中系统地检查这种关系。BLSA参与者在研究首次访视时认知正常（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。在拟定的研究中，我们将在BLSA研究的三次早期访视（大约间隔5年）、55岁及以上受试者（n=1095）、末次访视以及神经影像子研究期间测量血脂水平（鞘脂、脂肪酸、胆固醇和胆固醇酯）。具体目的包括检查拟定的外周脂质、这些脂质在长期随访中的变化及其与ApoE的相互作用，以预测：1）记忆力测试下降; 2）突发MCI、全因痴呆和AD; 3）10年内脑萎缩和白色病变负荷的系列MRI测量值变化; 4）11 C-PIB PET扫描上的β淀粉样蛋白沉积。将使用已开发的靶向和定量脂质组学方法测定脂质。 公共卫生相关性：阿尔茨海默病（AD）的许多潜在风险因素，包括高血压和高胆固醇，在中年最有害，可能是在AD病理学出现时，但对晚年AD风险的影响较小。在中年确定因素，可能会改变APOE E4在启动AD病理的影响，以及随后出现的症状，将独特地有助于预防策略的发展。拟议研究的总体目的是在为期50年的巴尔的摩老龄化纵向研究中，检查中年时测量的血浆脂质（鞘脂、神经节苷脂、脂肪酸、胆固醇和胆固醇酯）是否改变APOE与认知功能减退、轻度认知功能障碍或AD临床发作以及脑萎缩和脑病理学的神经影像学指标之间的关联。