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（由申请人提供）：载脂蛋白E（ApoE）基因的E4等位基因是迄今为止确定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 在 AD 发病机制中影响淀粉样蛋白-β (A2) 代谢和非 A2 介导机制的作用仍有待完全阐明。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）的早期变化反映了大脑功能和病理学，并且可能与 AD 发病机制发展中的 ApoE 基因型相互作用，值得进行人体研究。短期的临床和流行病学研究虽然很重要，但无助于我们了解 AD 发病机制的最早阶段，因为阿尔茨海默病的病理学（A2 斑块和神经原纤维缠结）在症状和严重神经变性出现前几十年就开始了。在 AD 发病前数年确定可能改变 ApoE4 在引发和促进 AD 病理学以及随后症状出现中的作用的因素，将为预防策略的制定做出独特贡献。正如 1958 年发起的巴尔的摩纵向衰老研究 (BLSA) 的独特队列中所提出的那样，对认知正常个体进行一系列活体大脑中阿尔茨海默病病理学测量的纵向研究对于了解 ApoE4 基因型、扰动之间的关系是必要的。外周血脂、它们的相互作用以及 AD 临床症状和大脑改变的后期发展。 BLSA 是为数不多的能够提供前所未有的机会在长期随访中系统地检验这种关系的人类研究之一。 BLSA 参与者首次参与研究时认知正常（平均年龄：63.4），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 3 次早期访视时测量 55 岁及以上 (n=1095) 的血浆脂质水平（鞘脂、脂肪酸、胆固醇和胆固醇酯），大约相隔 5 年。最后一次访问以及神经影像子研究期间。具体目标包括检查所提出的外周脂质、这些脂质在长期随访中的变化以及它们与 ApoE 的相互作用，以预测：1）记忆测试下降； 2) 偶发 MCI、全因痴呆和 AD； 3）10年来脑萎缩和白质病变负担的连续MRI测量变化； 4) 11C-PIB PET 扫描中的β淀粉样蛋白沉积。将使用已经开发的靶向定量脂质组学方法对脂质进行分析。 公共健康相关性：阿尔茨海默病 (AD) 的许多潜在危险因素，包括高血压和高胆固醇，在中年时最为有害，大概是在 AD 病理出现时，但对晚年 AD 风险的影响较小。确定中年时期可能改变 APOE E4 在引发 AD 病理学以及随后症状出现中的影响的因素，将为预防策略的制定做出独特贡献。拟议研究的总体目标是在为期 50 年的巴尔的摩纵向衰老研究中检验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）是否会改变 APOE 与认知之间的关联衰退、轻度认知障碍或 AD 的临床发作，以及脑萎缩和脑病理学的神经影像学测量。