Longitudinal Study of Lipids and APOE in the Development of AD and AD 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散发性阿尔茨海默病（AD）发病的最强遗传危险因素。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，早期外周脂质（鞘脂、脂肪酸、胆固醇和胆固醇酯）的改变反映了脑功能和病理，并可能与ApoE基因型在AD发病机制的发展中相互作用，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）在症状和实质性神经退行性变出现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ApoE4在启动和促进阿尔茨海默病病理和随后症状出现中的作用的因素，将独特地有助于制定预防策略。在1958年开始的巴尔的摩衰老纵向研究（BLSA）的独特队列中，有必要对认知正常的个体进行纵向研究，并在活脑中测量阿尔茨海默病的病理，以了解ApoE4基因型，外周脂质扰动，它们的相互作用以及AD临床症状和大脑改变的后期发展之间的关系。BLSA是为数不多的人类研究之一，它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参与者在研究中首次访问时认知正常（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研究的三次早期访问中测量血浆脂质水平（鞘脂、脂肪酸、胆固醇和胆固醇酯），大约间隔5年，年龄在55岁及以上的人（n=1095），最后一次访问以及神经影像学子研究期间。具体目的包括检查外周脂质，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)记忆力测试的下降；2) MCI、全因痴呆和AD的发生；3) 10年间脑萎缩和白质病变负荷的MRI序列测量变化；11C-PIB PET扫描显示淀粉样蛋白沉积。脂质将使用已经开发的靶向定量脂质组学方法进行分析。

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.