Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig Maximilian University (LMU), Munich, Germany.
Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.
Mol Neurodegener. 2020 Oct 8;15(1):57. doi: 10.1186/s13024-020-00407-2.
The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.
We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).
Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f = 0.137) and memory decline (p = 0.006, Cohen's f = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ, p-tau). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.
Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.
载脂蛋白 E ε4 等位基因（即 ApoE4）是散发性阿尔茨海默病（AD）最强的遗传风险因素。TREM2（即髓样细胞触发受体 2）是一种在大脑中表达的小胶质细胞跨膜蛋白，在 AD 脑病理学引起的小胶质细胞激活中起核心作用。较高的 TREM2 相关小胶质细胞活性是否会降低发生临床 AD 的风险，这是一个悬而未决的问题。因此，本研究的目的是评估较高的可溶性 TREM2 是否会减弱 ApoE4 对未来认知能力下降和神经退行性变的影响。
我们纳入了来自阿尔茨海默病神经影像学倡议的 708 名认知正常（CN，n=221）、轻度认知障碍（MCI，n=414）和 AD 痴呆（n=73）的受试者。我们使用线性回归来测试 ApoE4 携带与脑脊液评估的 sTREM2 水平作为预测因素之间的相互作用，以评估纵向评估的认知能力下降和 MRI 评估的海马体积变化（平均随访 4 年，范围为 1.7-7 年）。
在整个样本中，我们发现基线时较高的 CSF sTREM2 与 ApoE4 携带的衰减作用相关（即 sTREM2 x ApoE4 相互作用），包括纵向整体认知（p=0.001，Cohen's f=0.137）和记忆下降（p=0.006，Cohen's f=0.104）以及纵向评估的海马萎缩（p=0.046，Cohen's f=0.089），独立于 CSF 中 AD 主要病理学标志物（即 Aβ、p-tau）。虽然 sTREM2 的总体作用较小，但按诊断组分层的探索性亚分析表明，sTREM2 的有益作用在 MCI 组中更为明显。
我们的结果表明，较高的 CSF sTREM2 水平与减弱 ApoE4 相关的未来认知能力下降和 AD 典型神经退行性变的风险有关。这些发现提供了进一步的证据，表明 TREM2 可能对 AD 的发展具有保护作用。
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