A brain atlas maps shared and distinct changes across eight disorders
Gene activity in more than 6.3 million brain-cell nuclei reveals links among neurodegenerative and psychiatric diseases.
Editorial illustration — not from the study.
The study mapped gene activity across brain cells from donors with Alzheimer’s disease, diffuse Lewy body disease, vascular dementia, Parkinson’s disease, tauopathy, frontotemporal dementia, schizophrenia and bipolar disorder, along with neurotypical controls. Differences between people accounted for a substantial share of the variation in gene activity, but the researchers also identified patterns shared across disorders.
After accounting for these broad patterns, Alzheimer’s disease, diffuse Lewy body disease, vascular dementia and Parkinson’s disease showed stronger genetic and gene-activity similarities. In Alzheimer’s disease, more severe cases had fewer neurons and more immune and blood-vessel-related cells, while certain deep-layer excitatory neurons were more abundant in donors with a range of neuropsychiatric symptoms.
What the atlas found
The researchers generated a single-cell atlas from the dorsolateral prefrontal cortex using specimens from 1,494 unique donors and more than 6.3 million individual nuclei. The donors included neurotypical controls and people affected by eight disorders: Alzheimer’s disease, diffuse Lewy body disease, vascular dementia, Parkinson’s disease, tauopathy, frontotemporal dementia, schizophrenia and bipolar disorder.
Variation between individuals explained a substantial portion of differences in gene activity. Across diseases, shared signatures were enriched in basic cell functions, including the processing of messenger RNA and the transport of proteins within cells. Once these common signatures were removed, Alzheimer’s disease, diffuse Lewy body disease, vascular dementia and Parkinson’s disease showed stronger genetic and gene-activity concordance.
Among different Alzheimer’s disease phenotypes, the researchers identified changes that differed from healthy ageing. More severe Alzheimer’s disease was associated with a reduction in neuronal abundance and increases in immune and vascular cell populations. A greater abundance of deep-layer excitatory neurons was associated with a broad range of neuropsychiatric symptoms. Disease-progression trajectories also pointed to cell-type-specific responses at early and late stages of Alzheimer’s disease.
Why the comparisons matter
The atlas offers a way to compare molecular changes across several neurodegenerative and neuropsychiatric disorders in the same brain region. It highlights both shared processes and differences between diseases, including changes involving nerve cells, immune cells and vascular cells.
By separating broad cross-disease patterns from disease-related signals, the work may help researchers identify biological processes for further study and possible therapeutic targets. The findings also distinguish molecular changes linked with Alzheimer’s disease severity and symptoms from changes seen in healthy ageing.
Evidence and limits
This is a large human tissue study based on single-cell measurements of gene activity in brain specimens. It provides a detailed description of associations among cell types, diseases, symptoms and disease stages, but it does not by itself establish that the observed gene-activity changes cause disease or symptoms, or that any identified target will improve treatment.
The atlas focuses on the dorsolateral prefrontal cortex and the eight disorders represented in the donor cohort. It also reports substantial variation between individuals, which is important when interpreting patterns across diseases and Alzheimer’s disease phenotypes. The abstract does not provide enough information to assess how representative the donors were of all people with these conditions.
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