Single-Cell Transcriptomics in Neurodegenerative Disorders

Single-cell transcriptomics has revolutionised our understanding of the cellular complexity underlying neurodegenerative disorders by enabling the high-resolution profiling of individual brain cells. This approach captures the diverse transcriptional states of neurons, glia and vascular cells, revealing how each population contributes to disease onset and progression. In Alzheimer’s disease, for example, distinct microglial subpopulations emerge that are closely associated with amyloid-β or tau pathology, while reactive astrocytes display heterogeneous inflammatory and proteostatic programmes. Oligodendrocyte precursor cells show remyelination responses in early stages but fail to sustain myelin integrity as disease advances. Single-nucleus RNA sequencing applied to genetic forms of disease uncovers variant-specific transcriptional signatures, such as dysregulated autophagy in TREM2-associated oligodendrocytes or ferroptosis in APOEε4-bearing inhibitory neurons. Spatially resolved transcriptomics further maps these cellular states within affected brain regions, highlighting local vulnerability and inter-cellular communication networks. Collectively, single-cell approaches elucidate cell-type-specific pathways, nominate novel therapeutic targets and inform the development of precision interventions in neurodegeneration.

Research from Nature Portfolio

Recent studies have generated a multimodal atlas of the middle temporal gyrus in Alzheimer’s disease, integrating single-cell and spatial genomics with quantitative neuropathology. This work delineates an early phase marked by inflammatory microglia, reactive astrocytes and remyelinating oligodendrocyte precursors, followed by a later phase characterised by the loss of excitatory and inhibitory neurons. Complementary single-nucleus RNA sequencing of autosomal dominant Alzheimer’s and risk variant carriers has revealed cell-type-specific dysregulation: TREM2-linked oligodendrocytes exhibit autophagy-lysosomal defects, MS4A-driven microglia show altered complement gene expression and APOEε4 neurons undergo susceptibility to ferroptosis. Deep profiling of human microglia in Alzheimer’s cortex has identified both established and novel microglial phenotypes, inferred gene regulatory networks driving these states and potential developmental trajectories, offering insight into how innate immune cells evolve during neurodegeneration.

Single-Cell Transcriptomics in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in single-cell transcriptomics in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Single-cell transcriptomics: High-throughput analysis of gene expression in individual cells.

Single-nucleus RNA sequencing (snRNA-seq): Transcriptome profiling of isolated nuclei, enabling studies of frozen or archived brain tissue.

Spatial transcriptomics: Mapping of gene expression patterns within intact tissue sections to preserve anatomical context.

Microglia: Innate immune cells of the central nervous system involved in surveillance and response to pathology.

Astrocytes: Glial cells that maintain neuronal homeostasis, regulate blood–brain barrier function and respond to injury.

Oligodendrocyte precursor cells (OPCs): Progenitor cells responsible for generating myelinating oligodendrocytes.

Gene regulatory network: A collection of molecular interactions that control gene expression in a cell.

Autophagy-lysosomal pathway: Cellular degradation system that recycles damaged organelles and proteins.

Ferroptosis: A form of iron-dependent cell death driven by lipid peroxidation.

References

1. Integrated multimodal cell atlas of Alzheimer’s disease. Nature Neuroscience (2024).
2. Mechanisms of astrocyte aging in reactivity and disease. Molecular Neurodegeneration (2025).
3. Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers. Nature Communications (2023).
4. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America (2020).
5. Distinct amyloid-β and tau-associated microglia profiles in Alzheimer’s disease. Acta Neuropathologica (2021).
6. Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology. Acta Neuropathologica (2021).
7. Human microglia show unique transcriptional changes in Alzheimer’s disease. Nature Aging (2023).
8. Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease. Acta Neuropathologica Communications (2022).
9. Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease. Genome Medicine (2022).