Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ40, worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ1-38, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.

中文翻译：

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MS4A 簇中的变体与神经病理学生物标志物上可溶性 TREM2 表达相互作用


最近的证据表明，MS4A 位点的阿尔茨海默病 (AD) 遗传风险变异（rs1582763 和 rs6591561）是全基因组范围内可溶性 TREM2 水平的重要调节因子，因此保护性变异 (rs1582763) 的次要等位基因与较高的 sTREM2 和较低的 sTREM2 相关。 AD 风险，而 (rs6591561) 的次要等位基因与较低的 sTREM2 和较高的 AD 风险相关。我们的小组之前发现，较高的 sTREM2 与较高的 Aβ40、较差的血脑屏障 (BBB) 完整性（用脑脊液/血浆白蛋白比率测量）和较高的脑脊液 tau 相关，表明与淀粉样蛋白丰度密切相关，而血脑屏障和神经退行性变使解释变得复杂。我们通过利用这些常见变异作为遗传工具来调整高 CSF sTREM2 的解释，并探索这些变异对 CSF sTREM2 以及大脑中 TREM2 转录水平之间已确立的关联的潜在修改作用，从而扩展了这项工作与 AD 神经病理学。 Biomarker 分析了范德比尔特记忆与衰老项目（n = 127，年龄 = 72 ± 6.43）的杠杆数据，并在阿尔茨海默病神经影像计划（n = 399，年龄 = 73 ± 7.39）中进行了复制。利用宗教团体研究和 Rush Memory and Aging Project 的数据进行尸检分析（n = 577，年龄 = 89 ± 6.46）。我们发现保护性变体 rs1582763 减弱了 CSF sTREM2 和 Aβ40 之间的关联（β = -0.44，p 值 = 0.017），并在 ADNI 中复制了这种相互作用（β = -0.27，p = 0.017）。我们没有观察到脑中 TREM2 mRNA 水平和 Aβ 肽之间存在相同的相互作用效应（Aβ 总 β = -0.14，p = 0.629；Aβ1-38，β = 0.11，p = 0.200）。 与对 Aβ 的影响相反，该相同变体的次要等位基因似乎增强了与血脑屏障功能障碍的关联（β = 7.0e-4，p = 0.009），这表明 sTREM2 升高可能在该等位基因的携带者与非携带者。在评估跨数据集的风险变异 (rs6591561) 时，我们没有观察到与 VMAP 中任何结果存在统计上显着的交互作用，并且观察到 ADNI 和 ROS/MAP 与 Aβ 水平的关联方向相反。总之，我们的结果表明 rs1582763 的保护作用可能通过解耦 sTREM2 和淀粉样蛋白丰度之间的关联来发挥作用，为 sTREM2 变化提供重要的机制见解，并强调将遗传背景纳入 sTREM2 水平分析的必要性，特别是如果将其用作未来疾病的临床生物标志物。