Philippi Sarah M, Bp Kailash, Raj Towfique, Castellano Joseph M
Nash Family Department of Neuroscience, Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ann Clin Transl Neurol. 2025 Feb;12(2):366-382. doi: 10.1002/acn3.52250. Epub 2024 Dec 17.
Recent work has bolstered the possibility that peripheral changes may be relevant to Alzheimer's disease pathogenesis in the brain. While age-associated blood-borne proteins have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here, we investigate whether APOE allelic variation or presence of brain amyloid are associated with plasma proteomic changes and the molecular processes associated with these changes.
Using the SOMAscan assay, we measured 1305 plasma proteins from 53 homozygous, APOE3 and APOE4 subjects without dementia. We investigated the relationship of either the APOE-ε4 allele or amyloid positivity with plasma proteome changes by linear mixed effects modeling and ontology-based pathway and module-trait correlation analyses.
APOE4 is associated with plasma protein differences linked to atherosclerosis, tyrosine kinase activity, cholesterol transport, extracellular matrix, and synaptogenesis pathways. Independent of APOE4, we found that subjects likely harboring brain amyloid exhibit plasma proteome signatures associated with AD-linked pathways, including neurovascular dysfunction.
Our results indicate that APOE4 status or presence of brain amyloid are associated with plasma proteomic shifts prior to the onset of symptoms, suggesting that systemic pathways in certain risk contexts may be plausible targets for disease modification.
近期的研究支持了外周变化可能与阿尔茨海默病大脑发病机制相关的可能性。虽然与年龄相关的血源性蛋白已成为恢复衰老大脑功能的靶点，但尚不清楚其他功能失调的全身状态是否也能带来类似益处。在此，我们研究了APOE等位基因变异或脑淀粉样蛋白的存在是否与血浆蛋白质组变化以及与这些变化相关的分子过程有关。
我们使用SOMAscan检测法，对53名无痴呆的纯合子、APOE3和APOE4受试者的1305种血浆蛋白进行了测量。我们通过线性混合效应模型以及基于本体的通路和模块-性状相关性分析，研究了APOE-ε4等位基因或淀粉样蛋白阳性与血浆蛋白质组变化之间的关系。
APOE4与血浆蛋白差异相关，这些差异与动脉粥样硬化、酪氨酸激酶活性、胆固醇转运、细胞外基质和突触发生通路有关。独立于APOE4，我们发现可能存在脑淀粉样蛋白的受试者表现出血浆蛋白质组特征，这些特征与包括神经血管功能障碍在内的与阿尔茨海默病相关的通路有关。
我们的结果表明，APOE4状态或脑淀粉样蛋白的存在与症状出现之前的血浆蛋白质组变化有关，这表明在某些风险情况下，全身通路可能是疾病修饰的合理靶点。
