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。需要充分了解阿尔茨海默病(AD)的复杂性 使用淀粉样蛋白、tau蛋白和神经元以外的生物标记物更准确地描述AD的病理生理学特征 伤害(AT[N])。血管病变大大增加了AD和AD相关痴呆(ADRD)的风险 在大多数AD/ADRD病例中，与AD病理(脑淀粉样沉积)共存。 神经炎症是血管和AD病理发展的基础，并由 加剧或减轻认知衰退的外围因素。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发展的相关因素 神经炎症、神经变性和AD/ADRD后遗症(认知功能减退和偶发痴呆)。 这项建议的目的是确定与血浆脂蛋白相关的蛋白质和脂类 与AD病理、血管病理、神经炎症、神经退行性变、认知功能减退和事件 老年人的痴呆症。中心假设是血浆脂蛋白影响脑淀粉样蛋白 沉积、血管病理和神经炎症，并改变神经退行性变和运动轨迹 认知功能减退与偶发性痴呆。这项拟议的研究将使用已经收集的血浆样本 以及来自社区动脉粥样硬化风险神经认知研究(ARIC-NCS)的结果数据。我们 确定了743名符合条件的非痴呆ARIC-NCS参与者(平均年龄：76.4岁)，他们有血液 在基线时收集，并进行基线血浆淀粉样蛋白沉积(Ab42/40比率，p-tau)的测量 181)、神经炎症(GFAP)和神经变性(NFL)。这些参与者还拥有中央 动脉僵硬、认知功能和状态在基线时评估，与基线血液同时进行 我们将用于我们的血浆脂蛋白分离的集合，并具有认知功能和地位 在平均6.5年的随访期内再评估两次。我们将随机挑选346名参与者 分离他们的血浆样本，测量1384个分离的血浆脂蛋白中的蛋白质和血脂(346个 每一组分[极低密度脂蛋白，极低密度脂蛋白，低密度脂蛋白，高密度脂蛋白])分别使用基于MS的蛋白质组学和脂质组学，并鉴定 血浆脂蛋白中的蛋白质、脂质或其相互作用与AD/ADRD相关结局的关系。这个 具体目的是：1)测定分离的血浆脂蛋白中的蛋白质或脂类，作为指示 AD病理学和血管病理学；2)在分离的血浆脂蛋白中建立蛋白质或脂类为 提示神经炎症和神经退行性变的生物标志物；以及3)识别蛋白质或脂肪 分级血浆脂蛋白作为预测认知功能减退和痴呆发生的生物标志物。我们的 建议将拓宽我们的视角和对AD/ADRD发展中的外围因素的理解 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 超越当前治疗或预防AD/ADRD的AT[N]范例的生物标志物。

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.