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

项目摘要。关键需要存在充分了解阿尔茨海默病（AD）的复杂性 病理生理学，并使用淀粉样蛋白、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]）。血管病变显著增加AD和AD相关痴呆（ADRD）的风险 并且在大多数AD/ADRD病例中与AD病理学（脑淀粉样蛋白沉积）共存。 神经炎症是血管和AD病理学发展的基础，并通过以下方式调节： 加重或减弱认知能力下降的外围因素。有证据表明血浆脂蛋白 影响脑淀粉样蛋白沉积和脑小血管疾病的发展， 神经炎症、神经变性和AD/ADRD后遗症（认知下降和偶发性痴呆）。 本提案的目的是鉴定血浆脂蛋白的蛋白质和脂质货物， AD病理学、血管病理学、神经炎症、神经变性、认知衰退和偶发事件 老年痴呆症中心假设是血浆脂蛋白影响脑淀粉样蛋白 沉积，血管病理学和神经炎症，并改变神经变性和轨迹， 认知能力下降和痴呆症本拟定研究将使用已采集的血浆样本 以及来自社区神经认知研究（ARIC-NCS）中动脉粥样硬化风险的结果数据。我们 确定了743名符合条件的ARIC-NCS参与者，他们没有痴呆症（平均年龄：76.4岁）， 在基线时收集并具有脑淀粉样蛋白沉积（Ab 42/40比率，p-tau 181）、神经炎症（GFAP）和神经变性（NfL）可用。这些参与者也有中央 基线时评价的动脉硬度和认知功能及状态，与基线血液检查同时进行 收集，我们将用于我们的血浆脂蛋白分馏，并有认知功能和状态 在平均6.5年的随访期内进行了两次以上的评估。我们将随机选择346名参与者， 对他们的血浆样品进行分级，测量1384个分级血浆脂蛋白中的蛋白质和脂质（346个 每个组分[VLDL，IDL，LDL，HDL]）分别使用基于MS的蛋白质组学和脂质组学，并鉴定 蛋白质、脂质或血浆脂蛋白中它们的相互作用与AD/ADRD相关结局的关系。的 具体的目的是：1）确定分级血浆脂蛋白中的蛋白质或脂质作为指示 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变性的生物标志物;和3）鉴定神经炎症和神经变性中的蛋白质或脂质。 分级血浆脂蛋白作为预测认知能力下降和痴呆事件的生物标志物。我们 建议将拓宽我们对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血浆脂蛋白为基础的治疗策略， 在治疗或预防AD/ADRD方面，目前的AT[N]范式之外的生物标志物。

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.