Epigenetic and transcriptomic alterations precede amyloidosis in the Alzheimer's disease AppNL-G-F knock-in mouse model.

Understanding Alzheimer's disease (AD) from its earliest stages is essential for uncovering initial mechanisms of pathology and developing interventions. Here, we use the humanized AppNL-G-F mouse model, which develops early amyloid pathology along a predictable timeline, to characterize epigenetic changes in the brain and blood at early pre-symptomatic, as well as later, stages of disease progression. We identified alterations in chromatin accessibility, gene expression, and DNA methylation before and after amyloidosis, in the absence of advanced age. Despite broadly stable hippocampal cell composition, AppNL-G-F mice exhibit major gene expression differences preceding amyloid plaque deposition, particularly in pathways related to mitochondrial function and protein biosynthesis. In later stages of pathology, immune pathways were upregulated, consistent with established neuroinflammatory processes in AD. Extensive DNA methylation changes were also detected in both blood and hippocampus at early and late pathology stages. Many blood methylation differences at early stages overlapped brain cis-regulatory elements and mapped near differentially expressed hippocampal genes, with enrichment in neuronal development and synaptic pathways, underscoring a potential link between blood methylation and brain physiology and supporting the potential of blood DNA methylation as an early biomarker of amyloidosis. Notably, five genes, including Rbfox1 and Camta1, showed coordinated epigenetic dysregulation in both brain and blood prior to amyloidosis, highlighting them as potential early blood-based biomarkers.