Identification of plasma lipoprotein proteins and lipids as biomarkers of innate-immunity and vascular contributions to Alzheimer's disease and Alzheimer's disease-related dementias in older adults

鉴定血浆脂蛋白和脂质作为老年人阿尔茨海默病和阿尔茨海默病相关痴呆的先天免疫和血管贡献的生物标志物

• 批准号: 10660037
• 负责人: Danni Li
• 金额: $ 223.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660037
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-Protein; Amyloid deposition; Apolipoprotein E; Apolipoproteins; Atherosclerosis Risk in Communities; Attenuated; Biological; Biological Markers; Blood; Blood Vessels; Blood specimen; Brain; Cardiovascular system; Cerebral small vessel disease; Collection; Combined Modality Therapy; Complement component C6; Complex; Data; Dementia; Development; Elderly; Eligibility Determination; Failure; Fractionation; Functional disorder; Genotype; Glial Fibrillary Acidic Protein; Goals; High Density Lipoproteins; IDL lipoproteins; Impaired cognition; Incidence; Light; Lipids; Lipoproteins; Low-Density Lipoproteins; Mass Spectrum Analysis; Measures; Memory; Natural Immunity; Nerve Degeneration; Neurocognitive; Neuronal Injury; Outcome; Participant; Pathology; Patients; Peripheral; Plasma; Prevention; Proteins; Proteomics; Random Allocation; Sampling; Therapeutic; Threonine; Time; Vascular Diseases; Vascular System; Very low density lipoprotein; arterial stiffness; brain volume; cognitive function; executive function; follow-up; human old age (65+); lipidomics; neurofilament; neuroinflammation; novel therapeutic intervention; precision medicine; predictive marker; prevent; protective effect; sex; tau Proteins; tau-1; treatment strategy; vascular contributions

Project Summary. Critical needs exist to fully understand the complexity of Alzheimer’s disease (AD) pathophysiology and more accurately characterize AD using biomarkers beyond amyloid, tau, and neuronal injury (AT[N]). Vascular pathology substantially increases the risk of AD and AD-related dementias (ADRDs) and coexists with AD pathology (brain amyloid deposition) in the majority of AD/ADRD cases. Neuroinflammation underlies the development of both vascular and AD pathologies and is modulated by peripheral factors that exacerbate or attenuate cognitive decline. Evidence suggests that plasma lipoproteins influence the development of brain amyloid deposition and cerebral small vessel diseases and underlying neuroinflammation, neurodegeneration, and AD/ADRD sequelae (cognitive decline and incident dementia). The objective of this proposal is to identify protein and lipid cargo of plasma lipoproteins that are associated with AD pathology, vascular pathology, neuroinflammation, neurodegeneration, cognitive decline, and incident dementia in older adults. The central hypotheses are that plasma lipoproteins influence brain amyloid deposition, vascular pathology, and neuroinflammation, and alter neurodegeneration and trajectories of cognitive decline and incident dementia. This proposed study will employ already-collected plasma samples and outcome data from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). We identified 743 eligible ARIC-NCS participants without dementia (mean age: 76.4 years) who had blood collected at baseline and had baseline plasma measures of brain amyloid deposition (Ab 42/40 ratio, p-tau 181), neuroinflammation (GFAP), and neurodegeneration (NfL) available. These participants also had central arterial stiffness and cognitive function and status evaluated at baseline, concurrent with the baseline blood collection that we will use for our plasma lipoprotein fractionation, and had cognitive function and status evaluated twice more over a mean follow-up period of 6.5 years. We will randomly select 346 participants and fractionate their plasma samples, measure proteins and lipids in 1384 fractionated plasma lipoproteins (346 of each fraction [VLDL, IDL, LDL, HDL]) using MS-based proteomics and lipidomics, respectively, and identify proteins, lipids, or their interactions in plasma lipoproteins in relation to AD/ADRD-related outcomes. The specific aims are: 1) Determine proteins or lipids in fractionated plasma lipoproteins as biomarkers indicative of AD pathology and vascular pathology; 2) Establish proteins or lipids in fractionated plasma lipoproteins as biomarkers suggestive of neuroinflammation and neurodegeneration; and 3) Identify proteins or lipids in fractionated plasma lipoproteins as biomarkers predictive of cognitive decline and incident dementia. Our proposal will broaden our perspective and understanding of peripheral factors in the development of AD/ADRD pathophysiology and will identify potentially useful plasma lipoprotein–based therapeutic strategies and biomarkers beyond the current AT[N] paradigm for treating or preventing AD/ADRDs.

项目摘要 充分了解阿尔茨海默病 (AD) 的复杂性存在关键需求。 使用淀粉样蛋白、tau 蛋白和神经元以外的生物标志物更准确地表征 AD 损伤 (AT[N]) 会显着增加 AD 和 AD 相关痴呆 (ADRD) 的风险。 在大多数 AD/ADRD 病例中，与 AD 病理（脑淀粉样蛋白沉积）并存。 神经炎症是血管和 AD 病理发展的基础，并受以下因素调节： 有证据表明，血浆脂蛋白会加重或减轻认知能力下降。 影响脑淀粉样蛋白沉积和脑小血管疾病的发展及其潜在 神经炎症、神经变性和 AD/ADRD 后遗症（认知能力下降和痴呆）。 该提案的目的是鉴定与相关的血浆脂蛋白的蛋白质和脂质货物 与 AD 病理学、血管病理学、神经炎症、神经变性、认知能力下降和事件相关 老年人痴呆的中心假设是血浆脂蛋白影响大脑淀粉样蛋白。 沉积、血管病理学和神经炎症，并改变神经变性和轨迹 这项拟议的研究将使用已经收集的血浆样本。 以及社区神经认知研究中动脉粥样硬化风险 (ARIC-NCS) 的结果数据。 确定了 743 名符合条件且没有痴呆症的 ARIC-NCS 参与者（平均年龄：76.4 岁），他们有血液 在基线时收集并进行脑淀粉样蛋白沉积的基线血浆测量（Ab 42/40 比率、p-tau 181)、神经炎症 (GFAP) 和神经变性 (NfL) 这些参与者也有中枢神经系统疾病。 在基线时评估动脉僵硬度、认知功能和状态，与基线血液同时进行 我们将用于血浆脂蛋白分离的集合，并且具有认知功能和状态 在平均 6.5 年的随访期内，我们将随机选择 346 名参与者并进行两次评估。 分离血浆样本，测量 1384 种分离血浆脂蛋白（其中 346 种）中的蛋白质和脂质 分别使用基于 MS 的蛋白质组学和脂质组学分析每个组分 [VLDL、IDL、LDL、HDL]），并识别 蛋白质、脂质或其在血浆脂蛋白中的相互作用与 AD/ADRD 相关结果相关。 具体目标是： 1) 确定分级血浆脂蛋白中的蛋白质或脂质作为生物标志物指标 AD病理学和血管病理学；2)建立分级血浆脂蛋白中的蛋白质或脂质： 提示神经炎症和神经退行性变的生物标志物；以及 3) 识别其中的蛋白质或脂质； 分离血浆脂蛋白作为预测认知能力下降和痴呆的生物标志物。 该提案将拓宽我们对 AD/ADRD 发展的外围因素的视角和理解 病理生理学，并将确定潜在有用的基于血浆脂蛋白的治疗策略和 用于治疗或预防 AD/ADRD 的生物标志物超出了当前 AT[N] 范式。