On 1 May, researchers from the Broad Institute of MIT and Harvard published a landmark study in Nature, in which they profiled genetic changes in individual brain cells from people with Alzheimer’s disease (AD). Obtaining postmortem brain samples from participants enrolled in ROSMAP, a longitudinal cohort study of ageing and dementia, co-senior authors Li-Huei Tsai and Manolis Kellis performed single-cell RNA sequencing (scRNA-seq) analysis. scRNA-seq is a powerful high-resolution technique that is used to specifically profile gene expression levels in single cells, revealing changes that low-resolution ‘bulk’ sequencing techniques are unable to detect. This is of particular importance in AD, where the contribution of different brain cell types to disease development is not yet fully understood. The research team reasoned that scRNA-seq would allow them to precisely map gene expression changes that occur during AD development, providing new clues on the role of specific brain cells in this complex disease.
To perform this mapping exercise, they applied the scRNA-seq technique to over 80,000 single cells taken from prefrontal cortex samples of 24 male and female ROSMAP participants at different stages of AD development, comparing them to samples from an equivalent number of gender-matched healthy controls. scRNA-seq was able to discriminate between, and genetically profile an array of brain cell types, from neurons to astrocytes, microglia to oligodendrocytes and beyond. Interestingly, the researchers showed that many cell-specific gene expression changes occurred in early AD, unmasking molecular pathways that had previously been obscured when using low-resolution sequencing techniques. Underlining the value of scRNA-seq, some of these gene expression changes were correlated with clinical markers of AD severity, such as cognitive impairment and amyloid plaque burden. The most surprising finding, according to the researchers, was that cells from women with AD showed much more pronounced changes in gene expression – in some cases, in the opposite direction to cells from men with AD. Moving forwards, the research team will focus on validating these findings on a larger scale, with additional experimental follow-up studies.
