Researchers at the University of California (UC) Irvine have conducted a transcriptomics analysis of Alzheimer’s disease, looking at the spatial differences in gene expression found across the brains of patients with early-stage and late-stage Alzheimer’s, as well as Alzheimer’s disease in Down syndrome.
Their results, published in Nature Genetics, uncovered new clues about disease processes that are intimately tied to specific cell types and brain regions. The data could be used to prioritize gene targets with higher translational potential in clinical development, stated Vivke Swarup, PhD, associate professor at UC Irvine and senior author of the study.
“Individuals with Down syndrome over 65 years have an 80% risk of dementia. Despite shared features with sporadic Alzheimer’s, there are no single-cell or spatial transcriptomic studies comparing these populations,” Swarup elaborated.
“Focusing on Alzheimer’s disease in Down syndrome, as a genetic form of Alzheimer’s, (…) provides opportunities for comparative analyses to further our understanding of Alzheimer’s genetics. Our analyses uncovered shared and distinct transcriptomic changes and identified relationships between genetic risk and altered transcriptomic signatures.”
Swarup and colleagues used spatial transcriptomics and single-nucleus RNA sequencing to precisely determine gene expression across tissue samples of the human prefrontal cortex, one of the main areas of the brain affected by Alzheimer’s disease. This revealed differences in gene expression changes between Alzheimer’s patients with and without Down syndrome, as well as gene expression changes that were common to all.
These changes in gene expression followed patterns that were specific to certain brain locations and cell types. For instance, the QKI gene, previously identified as being upregulated in Alzheimer’s, was shown to only be upregulated in the upper layers of the cortical tissue.
The differential analysis of the human tissue samples also revealed a significant difference in the samples of early-stage Alzheimer’s as compared to late-stage Alzheimer’s and Alzheimer’s in Down syndrome samples. A large cluster of genes was found to be downregulated only in early-stage samples, possibly indicating the presence of a molecular cascade underlying the progression of the disease.
The researchers then proceeded to compare their findings in human samples with a mouse model of Alzheimer’s. Here, spatial transcriptomics and single-nucleus RNA sequencing were paired with fluorescent imaging of amyloid-β plaques to investigate any potential links between spatial changes in gene expression and amyloid pathology.
“While mouse models are the most common non-human model systems used to probe Alzheimer’s biology, recent clinical trial failures of disease-modifying drugs, which were successful in mouse models, have raised important questions about translatability of mouse findings to humans.”
The results showed that not all changes in gene expression seen in the mouse model of Alzheimer’s were recapitulated in human samples. Based on this data, the researchers compiled a list of spatial changes in gene expression associated with amyloid pathology that are conserved among species.
“The study presents a collection of species-conserved amyloid-associated genes, creating a foundation for future studies in Alzheimer’s disease and potentially facilitating the translation of in vitro and mouse model findings to clinical applications,” said Swarup.
