A single-nucleus multiome map of the human cerebellum with Alzheimer’s disease and related dementias

Although cerebellum is neuropathologically affected in Alzheimer's disease (AD) and AD-related dementia (ADRD), the cell type-specific genomic and epigenomic changes remain poorly understood. Here, we present single-nucleus multiome (RNA-seq and ATAC-seq) analysis of 103,861 nuclei isolated from both the cerebellum and frontal cortex of diseased individuals and cognitively healthy controls. We identify 431,834 significant peak-to-gene linkages across cell subtypes, revealing cis-regulatory elements linked to cell type-specific and disease-associated transcriptomic and regulatory network changes. Differential trajectory analysis pinpoints disease-associated genes in cerebellar granule cells, such as STMN1 and CLU. Integrating epigenomic, genetic, and three-dimensional genome data, we pinpoint two likely causal variants linked to SEZ6L2 in Purkinje cells and KANSL1 in granule cells. Through CRISPR interference in patient-derived cerebellar organoids, we show that silencing the variant-containing regulatory elements suppresses SEZ6L2 and KANSL1 expression, which perturbs neurodegeneration-associated gene programs. This cell type-specific regulatory landscape provides genomic and epigenomic insights into the pathological role of the cerebellum in AD/ADRD. Alzheimer’s disease affects multiple brain regions, but cerebellar cell type‑specific changes are poorly understood. Here, the authors use single‑nucleus multiomics to map disease‑associated regulatory alterations in cerebellar cell types and identify functional risk variants linked to neurodegeneration.