Anderson AG, Rogers BB, Loupe JM, Rodriguez-Nunez I, Roberts SC, White LM, Brazell JN, Bunney WE, Bunney BG, Watson SJ, Cochran JN, Myers RM, Rizzardi LF. Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements. Cell Genomics, February 2, 2023 Cell Genomics

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  1. This study brings us closer to zeroing in on the gene-level changes that are associated with AD within specific brain-cell classes by aligning them with corresponding transcriptional regulatory events. This adds an important piece to the puzzle. Many of the key genes, or gene pathways, identified here recapitulate prior findings in parallel studies; so, in a field with enormous datasets, needles in the haystack are emerging.

    However, I feel this study suffers from the classic issues of working in postmortem human tissue. It remains to be determined if these gene and transcriptional changes are cause, effect, or a secondary component in AD patients, and it's likely some combination of all three. This doesn't detract from the enhanced confidence this study brings to the growing list, but it cannot address how to interpret these data within the context of pathogenic mechanisms or drivers of disease.

    Fortunately, many of the critical gene pathways and transcription factors discussed are linked to specific cellular functions that can be measured, so ideally, these RNA-seq and related studies can be accompanied by functional assays measuring calcium handling, synaptic transmission and plasticity, protein mishandling, microglial activation and phagocytosis, and astrocytic signaling in cells derived from these patients, and confirmed using gene-editing toolkits. Linking gene-level changes with associated changes in function and pathological markers will hopefully be the next step in establishing and differentiating cause and effect at the molecular level.

    View all comments by Grace Stutzmann

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  1. Single-Nuclei Multi-omics Spots Wonky Gene Regulation