Abstract：
While immune function is known to play a mechanistic role in Alzheimer\'s disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aβ accumulation, including causal relationships with Aβ PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aβ accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.
摘要：
虽然已知免疫功能在阿尔茨海默病（AD）中起机械作用，外周循环中的免疫蛋白是否会影响淀粉样蛋白-β（Aβ）的进展速率-AD的主要特征-尚不清楚。在巴尔的摩衰老的纵向研究中，我们定量了血浆中的942种免疫蛋白，并鉴定了32种(包括CAT[过氧化氢酶]，CD36[CD36抗原]，和KRT19[角蛋白19]）与用正电子发射断层扫描（PET）测量的皮质Aβ积累率相关。候选蛋白子集的纵向变化也预测了Aβ的进展，以及一种蛋白质的中晚期（20年）轨迹，CAT,在社区动脉粥样硬化风险（ARIC）研究中，与晚期Aβ阳性状态相关。影响CAT血浆水平的遗传变异，CD36和KRT19预测的Aβ积累率，包括两个样本孟德尔随机化确定的AβPET水平的因果关系。除了与tauPET和血浆AD生物标志物变化相关外，以及人类小胶质细胞亚型和神经血管细胞在AD脑组织中的表达模式，我们发现31%的候选蛋白与ARIC中(20岁)或晚期(8岁)痴呆风险相关.我们的发现揭示了与纵向Aβ积累相关的血浆蛋白，并鉴定可能有助于AD病理生理学进展的特异性外周免疫介质。
