Icelandic Heart Association, Kopavogur, Iceland.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Nat Aging. 2024 Oct;4(10):1446-1464. doi: 10.1038/s43587-024-00693-1. Epub 2024 Aug 21.
A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status.
深入了解导致迟发性阿尔茨海默病（LOAD）的分子过程有助于发现生物标志物和药物靶点。我们使用高通量血清蛋白质组学在前瞻性基于人群的年龄、基因/环境易感性雷克雅未克研究（AGES）队列中对 5127 名冰岛老年人（平均年龄 76.6±5.6 岁）进行了研究，鉴定出了 303 种与中位随访 12.8 年的 LOAD 发病相关的蛋白。这些蛋白中超过 40%与 LOAD 相关，与 APOE-ε4 携带状态无关，与神经元过程有关，并且与大脑和脑脊液中的 LOAD 蛋白特征重叠。我们鉴定出 17 种蛋白，其与 LOAD 的关联强烈依赖于 APOE-ε4 的携带状态，并且在脑脊液中的关联也基本一致。值得注意的是，这四种蛋白（TBCA、ARL2、S100A13 和 IRF6）被 APOE-ε4 下调，但由于 LOAD 而被上调，这一发现在外集人群中得到了复制，可能反映了对疾病发作的反应。这些发现强调了 LOAD 临床前阶段失调的途径，包括与 APOE-ε4 状态独立和依赖的途径。
