Influence of genetic risk factors on biomarkers and cognitive decline in preclinical AD

遗传风险因素对临床前 AD 生物标志物和认知能力下降的影响

• 批准号: 9012507
• 负责人: ELIZABETH MORMINO
• 金额: $ 13.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2017-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9012507
• 关键词: Affect; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Biological Markers; Clinical; Clinical Trials; Communities; Data; Dementia; Disease; Early identification; Environment; Evaluation; General Hospitals; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genotype; Goals; Heterogeneity; Hippocampus (Brain); Image; Impaired cognition; Impairment; Individual; Inferior; K-Series Research Career Programs; Link; Longitudinal Studies; Magnetic Resonance Imaging; Massachusetts; Mediating; Mediation; Meta-Analysis; Mitochondria; Nerve Degeneration; Neurons; Neuropsychological Tests; Odds Ratio; Pathway interactions; Pattern; Positron-Emission Tomography; Process; Research; Research Personnel; Risk; Sampling; Staging; Symptoms; Temporal Lobe; Testing; Thick; Time; Training; Wolves; Work; abeta accumulation; aging brain; base; career; follow-up; genetic analysis; genetic risk factor; genome wide association study; improved; in vivo; insight; medical schools; neocortical; neuroimaging; neuroinflammation; novel; pre-clinical; public health relevance; risk variant; tau Proteins; tau aggregation; tau phosphorylation

 DESCRIPTION (provided by applicant): The career goal of the K01 candidate is to become an independent investigator conducting research that contributes to the prevention of Alzheimer's disease (AD) dementia through elucidating disease mechanisms and deriving individual risk profiles during the preclinical stage of the disease. The environment at Massachusetts General Hospital and Harvard Medical School is ideal for the candidate's training and proposed research, providing state-of-the-art imaging facilities and a world-renowned community of AD researchers and clinicians. During this K award, the candidate will extend her expertise in multimodal neuroimaging by receiving training in Tau PET imaging, and acquire expertise in genetic analyses to pursue a novel research path. The research plan proposed herein examines the influence of known genetic risk factors, specifically the APOE4 genotype and 21 non-APOE loci associated with clinical AD in large GWAS analyses, on the relationship between AD biomarkers and cognitive decline in clinically normal older individuals (CN). An understanding of genetic risk factors within CN is especially relevant given the ability to select CN with biomarker evidence of elevated Aβ (preclinical AD). Although longitudinal studies have converged to reveal that CN with preclinical AD are at heightened risk of subsequent clinical impairment, heterogeneity in decline exists within this group, such that some of these individuals remain clinically normal for an extended period of time. Identification of genetic risk factors that influence the time between initial Aβ accumulation and the onset of clinical symptoms will greatly enhance our understanding of preclinical AD and improve our ability to identify individuals most at- risk for cognitive decline. Although some of the effects of known genetic risk factors for AD dementia are undoubtedly mediated by elevated Aβ, we hypothesize that these factors also influence the AD trajectory by interacting with Aβ to accelerate downstream effects such as the accumulation of neocortical Tau, neurodegeneration, and cognitive decline. Thus, for an equivalent level of Aβ burden, an individual with high genetic risk may show greater neurodegeneration than an individual with low genetic risk. This line of research should provide insight into why some Aβ+ individuals are able to remain clinically normal for longer periods of time whereas other Aβ+ individuals rapidly progress to clinical impairment. We will investigate these hypotheses in a large sample of 1777 CN combined across the Harvard Aging Brain Study (N=277), the Anti- Amyloid in Asymptomatic AD Study (A4, N=1000) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Study (LEARN, N=500). All CN will complete amyloid PET, structural MRI, genotyping data, and longitudinal neuropsychological testing, and a large subset will additionally complete Tau PET imaging (N=827). Because disease-modifying strategies are most likely to be successful during the preclinical stage, elucidating AD disease mechanisms and deriving individual risk profiles during the preclinical stage will have tremendous impact on the prevention of AD.

 描述（由申请人提供）：K01 候选人的职业目标是成为一名独立研究者，开展研究，通过阐明疾病机制并得出疾病临床前阶段的个体风险概况，为预防阿尔茨海默病 (AD) 痴呆做出贡献。马萨诸塞州总医院和哈佛医学院的环境非常适合候选人的培训和拟议研究，提供最先进的成像设施以及世界知名的 AD 研究人员和临床医生社区。在获得 K 奖期间，候选人将通过接受 Tau PET 成像培训来扩展她在多模式神经影像方面的专业知识，并获得遗传分析方面的专业知识，以追求新颖的研究道路。本文提出的研究计划在大型 GWAS 分析中检查了已知遗传风险因素，特别是 APOE4 基因型和 21 个与临床 AD 相关的非 APOE 位点，对 AD 生物标志物与临床正常老年人 (CN) 认知能力下降之间关系的影响。鉴于能够利用生物标志物选择 CN，了解 CN 内的遗传风险因素尤其重要 Aβ 升高的证据（临床前 AD）。尽管纵向研究一致表明患有临床前 AD 的 CN 患者出现后续临床损伤的风险较高，但该组内存在下降的异质性，因此其中一些个体在较长时间内保持临床正常。识别影响 Aβ 初始积累和临床症状出现之间时间的遗传风险因素将极大地增强我们对临床前 AD 的理解，并提高我们识别最有认知能力下降风险的个体的能力。尽管已知遗传风险的一些影响 AD 痴呆的因素无疑是由 Aβ 升高介导的，我们假设这些因素也通过与 Aβ 相互作用来影响 AD 轨迹，加速下游效应，如新皮质 Tau 的积累、神经退行性变和认知能力下降。因此，对于同等水平的 Aβ 负荷，具有高遗传风险的个体可能比具有低遗传风险的个体表现出更严重的神经变性。这一系列研究应该可以深入了解为什么一些 Aβ+ 个体能够在较长时间内保持临床正常，而其他 Aβ+ 个体却迅速进展为临床损伤。我们将在哈佛大脑老化研究 (N=277)、无症状 AD 研究中的抗淀粉样蛋白研究 (A4，N=1000) 以及淀粉样蛋白风险和神经变性研究的纵向评估 (LEARN，N=500) 的 1777 CN 大样本中研究这些假设。所有 CN 将完成淀粉样蛋白 PET、结构 MRI、基因分型数据和纵向神经心理学测试，并且很大一部分将另外完成 Tau PET 成像 (N=827)。由于疾病缓解策略最有可能在临床前阶段取得成功，因此在临床前阶段阐明 AD 疾病机制并得出个体风险概况将对 AD 的预防产生巨大影响。