Belloy Michael E, Graff-Radford Jonathan, Greicius Michael D
NeuroGenomics and Informatics Center, Washington University School of Medicine, St.Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, St.Louis, MO, USA.
medRxiv. 2025 Mar 13:2025.03.10.25323519. doi: 10.1101/2025.03.10.25323519.
The e4 and e2 alleles are respectively the most risk increasing and risk decreasing, common genetic risk factors for Alzheimer's disease (AD). They strongly affect Aβ burden in the brain parenchyma, a core hallmark of AD, but also at the level of the brain vasculature, i.e. cerebral amyloid angiopathy (CAA), which in turn relates to increased risk for amyloid-related imaging abnormalities (ARIA) in *4 carriers when receiving anti-Aβ antibody treatments. This makes a highly pursued AD drug target. A crucial question in the field is whether it would be beneficial to either increase or decrease (particularly *4) levels. The answer from rodent work appears to converge on "decreasing levels", with initial human studies supporting this. Human genetic evidence however remains scarce and new insights are crucially needed to support clinical translation. Shade et al. 2024 conducted the largest to date genome-wide association study (GWAS) of various neuropathological traits, identifying a variant protective of CAA in the locus independent of *4 and *2 genotypes. Downstream analyses suggested this signal links to the nearby gene through local effects on methylation. We applaud the authors on their timely, relevant, and well-conducted study. Here, we extend on these findings, highlighting there is compelling evidence that their genetic signal for reduced CAA relates to an effect on reduced microglial expression, which would importantly support the evidence in favor of "decreasing levels" and further herald this promising therapeutic avenue, not just for AD, but also for CAA. We additionally provide complimentary results regarding this locus' association with CAA and AD risk from analyses that we conducted parallel to Shade et al. 2024.
E4和E2等位基因分别是阿尔茨海默病（AD）最易增加风险和最易降低风险的常见遗传风险因素。它们强烈影响脑实质中的Aβ负荷，这是AD的一个核心特征，而且在脑血管系统层面，即脑淀粉样血管病（CAA）中也有影响，而脑淀粉样血管病又与携带E4等位基因的个体在接受抗Aβ抗体治疗时出现淀粉样蛋白相关影像异常（ARIA）的风险增加有关。这使得它成为一个备受追捧的AD药物靶点。该领域的一个关键问题是，增加或降低（尤其是E4）水平是否有益。啮齿动物研究的答案似乎都指向“降低水平”，初步的人体研究也支持这一点。然而，人类遗传学证据仍然稀少，迫切需要新的见解来支持临床转化。Shade等人在2024年进行了迄今为止最大规模的关于各种神经病理学特征的全基因组关联研究（GWAS），确定了一个独立于E4和E2基因型的与CAA相关的保护性变异。下游分析表明，这个信号通过对甲基化的局部影响与附近的APOE基因相关联。我们对作者及时、相关且开展良好的研究表示赞赏。在此，我们扩展了这些发现，强调有令人信服的证据表明，他们发现的与CAA降低相关的遗传信号与小胶质细胞APOE表达降低的效应有关，这将重要地支持支持“降低APOE水平”的证据，并进一步预示着这条有前景的治疗途径，不仅对AD，而且对CAA都适用。我们还提供了与Shade等人在2024年平行进行的分析中关于该位点与CAA和AD风险关联的补充结果。
