Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin–gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

蛋白质聚集是神经变性的标志，但迟发性阿尔茨海默病 (AD) 的分子机制尚不清楚。在这里，我们整合了死后人脑的转录组、蛋白质组和表观基因组分析，以确定参与 AD 的分子途径。RNA 测序分析显示转录和染色质相关基因的上调，包括 H3K27ac 和 H3K9ac 的组蛋白乙酰转移酶。一项不偏不倚的蛋白质组学筛选将 H3K27ac 和 H3K9ac 作为 AD 特有的主要富集物。反过来，表观基因组分析揭示了组蛋白 H3 修饰 H3K27ac 和 H3K9ac 与 AD 中的转录、染色质和疾病途径相关的增益。在 AD 的苍蝇模型中增加全基因组 H3K27ac 和 H3K9ac 会加剧淀粉样蛋白-β42 驱动的神经变性。一起，这些发现表明 AD 涉及表观基因组的重新配置，其中 H3K27ac 和 H3K9ac 通过失调转录和染色质基因反馈环来影响疾病途径。这一过程的确定突出了早期疾病治疗的潜在表观遗传策略。