TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer’s disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD. A cross-sectional study of 1027 participants of the Alzheimer’s Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score. CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.

中文翻译：

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阿尔茨海默病中脑脊液 sTREM2 的早期增加与 tau 相关神经变性有关，但与淀粉样蛋白 β 病理学无关

TREM2是一种跨膜受体，主要由中枢神经系统中的小胶质细胞表达。TREM2 基因中的罕见变异会增加晚发性阿尔茨海默病 (AD) 的风险。可在脑脊液 (CSF) 中检测到由 TREM2 胞外域脱落产生的可溶性 TREM2 (sTREM2)，并且是 TREM2 介导的小胶质细胞功能的替代指标。先前已报道脑脊液 sTREM2 在 AD 的不同临床阶段增加，但是，与淀粉样蛋白 β-肽 (Aβ) 沉积或淀粉样蛋白级联中的其他病理过程（如 tau 病理或神经变性）相关的改变仍不清楚。在当前的横断面研究中，我们采用了 NIA-AA 共识指南最近提出的基于生物标志物的分类框架，结合临床分期，为了检查 AD 早期无症状和有症状阶段的 CSF sTREM2 改变。对阿尔茨海默病成像倡议 (ADNI) 队列的 1027 名参与者进行横断面研究，其中包括 43 名携带 TREM2 罕见遗传变异的受试者，使用先前验证的酶联免疫吸附测定 (ELISA) 测量脑脊液 sTREM2。ADNI 参与者按照 A/T/N 框架进行分类，我们根据 Aβ1-42 (A)、磷酸化 tau (T) 和总 tau 的 CSF 水平作为神经变性 (N) 的标志物在不同的临床阶段实施该框架由临床痴呆评分 (CDR) 评分定义。CSF sTREM2 在 TREM2 变体之间不同，而 p.R47H 变体具有更高的 CSF sTREM2，p.L211P 具有比非携带者更低的 CSF sTREM2。我们发现 CSF sTREM2 在迟发性 AD 的早期症状阶段增加，但出乎意料的是，当只有异常 Aβ 病理学 (A+) 但没有 tau 病理学或神经变性 (TN-) 时，我们观察到在最早的无症状期脑脊液 sTREM2 水平降低。展示。Aβ 病理学 (A) 和 tau 病理学/神经变性 (TN) 与 CSF sTREM2 有不同的关联。虽然 tau 相关神经变性与脑脊液 sTREM2 增加有关，但在没有下游 tau 相关神经变性的情况下，Aβ 病理与脑脊液 sTREM2 减少有关。Aβ 病理学 (A) 和 tau 病理学/神经变性 (TN) 与 CSF sTREM2 有不同的关联。虽然 tau 相关神经变性与脑脊液 sTREM2 增加有关，但在没有下游 tau 相关神经变性的情况下，Aβ 病理与脑脊液 sTREM2 减少有关。Aβ 病理学 (A) 和 tau 病理学/神经变性 (TN) 与 CSF sTREM2 有不同的关联。虽然 tau 相关神经变性与脑脊液 sTREM2 增加有关，但在没有下游 tau 相关神经变性的情况下，Aβ 病理与脑脊液 sTREM2 减少有关。