Neuronal and microglial fine-tuned 3D DNA foundation models dissect genetic variants in Alzheimer’s disease

Although genetic variants are among the strongest risk factors for Alzheimer’s disease (AD), most associated variants reside in non-coding regions with unclear mechanisms. Here, we address that gap by fine-tuning the Akita DNA foundation model on high-resolution Hi-C data generated from neuronal progenitor cells (NPCs) and microglia to produce iNeuroAkita , a cell-context-aware three-dimensional (3D) genome model. iNeuroAkita shows improved correlation with experimental Hi-C contact maps and more accurate contact predictions at key AD loci (e.g. APOE and PSEN2) , and captures CTCF-dependent chromatin loops. Using in silico saturation mutagenesis (ISM) across 11,856 AD-associated single-nucleotide variants (SNVs) and 120 structural variants (SVs), we quantified impacts on chromatin spatial organization and identified two SNVs predicted to strongly disrupt 3D chromatin architecture: rs636317 at the MS4A locus that is predicted to disrupt local chromatic interactions and microglia eQTL rs7599054 that creates gained interactions connecting its surrounding region to CCNT2 and TMEM163 , consistent with enhancer–promoter activation in epigenomic and single-cell transcriptomic data. We also identified AD-associated deletions at the KANSL1 and ARMS2 that rewire local regulatory contacts and associate with cell-type-specific expression changes, demonstrating iNeuroAkita’s utility for systematic characterization of noncoding AD risk variants underlying 3D genome regulation.