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.

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Publication Details

Journal
Nature Communications
Published
2026-10-14
DOI
https://doi.org/10.1038/s41467-026-78232-2
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Ming Hu, Margaret E. Flanagan, Rudolph J. Castellani, Feixiong Cheng et al.
Nature Communications
Single-cell and spatial transcriptomics
article

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

Ming Hu, Margaret E. Flanagan, Rudolph J. Castellani, Feixiong Cheng, Peter T. Nelson, Qinwen Mao, Borna Bonakdarpour, Lijun Dou, James B. Leverenz, Jeffrey L. Cummings, Yang Eric Li, Pouya Jamshidi, Andrew A. Pieper, Feng Yayan, William Robert Martin, Yunlong Liu, Xiaona Chu, Jielin Xu, Xiaoyu Yang, Hongyu Gao, Yuan Hou, Wenqiang Song, Xin Chen
article en

Abstract

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.

Nature Communications
Northwestern University (US), Cleveland Clinic (US), University of Nevada, Las Vegas (US), University of Arizona (US), University of Kentucky (US), The University of Texas at San Antonio Health Science Center (US), Washington University in St. Louis (US), University of Utah (US), Cleveland Clinic Lerner College of Medicine (US), VA Puget Sound Health Care System (US), Geriatric Research Education and Clinical Center (US), Indiana University Indianapolis (US), Indiana University School of Medicine, Indiana University – Purdue University Indianapolis (US), Case Western Reserve University (US)
National Institute on Aging
Good health and well-being
Openalex Percentile: Top 24%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
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