淀粉样前体蛋白及其血浆多肽与脑小血管病 神经影像标志物的因果关联——一项孟德尔随机化研究

Causal Associations between Amyloid Precursor Protein, Its Plasma Peptides, and Neuroimaging Markers of Cerebral Small Vessel Disease—A Mendelian Randomization Study

摘要: 目的：为明确血浆淀粉样蛋白标志物与脑小血管病(CSVD)的遗传因果关联，本研究整合孟德尔随机化(MR)与贝叶斯共定位分析开展系统探究。方法：基于大规模全基因组关联研究(GWAS)汇总统计数据，以血浆淀粉样前体蛋白(APP)、β-淀粉样蛋白40 (Aβ40)、β-淀粉样蛋白42 (Aβ42)及Aβ40/Aβ42比值为暴露因素，CSVD全谱系神经影像学亚型为结局指标，通过MR分析筛查因果关联，贝叶斯共定位分析验证可靠性。结果：经双重验证，Aβ40/Aβ42比值及Aβ42水平升高与脑白质高信号体积(WMHV)扩大、严格脑叶脑微出血(CMB)风险增加存在显著因果关联(均P < 0.05)，且在APOE基因rs429358位点存在极强共定位证据(PP.H4均>0.99)；MR分析显示APP水平升高与WMHV增加相关，Aβ42及Aβ40/Aβ42比值与各向异性分数(FA)降低以及平均弥散率(MD)升高相关，但未获共定位支持。反向MR分析未发现CSVD对血浆淀粉样蛋白标志物的反向因果效应。结论：血浆Aβ42水平升高及Aβ40/Aβ42比值失衡是CSVD脑白质损伤与脑叶CMB的独立因果风险因素，且受APOE基因调控；APP与CSVD的关联需进一步验证。本研究为CSVD早期标志物筛选与病因机制研究提供了遗传学证据。

Abstract: Objective: To elucidate the genetic causal associations between plasma amyloid biomarkers and cerebral small vessel disease (CSVD), we performed a systematic investigation by integrating Mendelian randomization (MR) and Bayesian colocalization analysis. Methods: Based on the summary statistics from large-scale genome-wide association studies (GWAS), we selected plasma amyloid precursor protein (APP), amyloid-β 40 (Aβ40), amyloid-β 42 (Aβ42), and the Aβ40/Aβ42 ratio as exposures, and the full spectrum of neuroimaging subtypes of CSVD as outcomes. MR analysis was performed to screen for potential causal associations, and Bayesian colocalization analysis was applied to validate the reliability of the identified associations. Results: Dual validation from both analyses confirmed that elevated Aβ40/Aβ42 ratio and Aβ42 levels were significantly causally associated with enlarged white matter hyperintensity volume (WMHV) and increased risk of strictly lobar cerebral microbleeds (all P < 0.05), with strong colocalization evidence at the rs429358 locus of the apolipoprotein E (APOE) gene (all posterior probability for hypothesis 4, PP.H4 > 0.99). MR analysis alone revealed that elevated APP levels were associated with increased WMHV, and elevated Aβ42 levels and Aβ40/Aβ42 ratio were associated with decreased fractional anisotropy (FA) and increased mean diffusivity (MD), while these associations were not supported by colocalization analysis. No reverse causal effect of CSVD on plasma amyloid biomarkers was detected in reverse MR analysis. Conclusion: Elevated plasma Aβ42 levels and imbalance of the Aβ40/Aβ42 ratio are independent causal risk factors for white matter injury and strictly lobar cerebral microbleeds in CSVD, and this effect is modulated by the APOE gene locus. The association between APP and CSVD requires further validation. This study provides genetic evidence for the identification of early biomarkers and the exploration of etiological mechanisms of CSVD.