In Alzheimer’s disease, toxic protein aggregates lead to neuroinflammation, and progressive loss of vulnerable synaptic connections and neurons, ultimately resulting in cognitive decline. Glial cells, particularly microglia and astrocytes, clear toxic protein aggregates and lipids, control inflammatory responses, and provide factors promoting neuronal survival and synapse function. Disruption of glial functions is emerging as critical driver of AD pathogenesis, but the underlying mechanisms remain poorly understood.  

Here, we present preliminary transcriptomic analyses of human tissue and stem cell models, identifying alterations of transcriptional programmes that may contribute to AD pathogenesis. We show that in stem-cell-derived microglia, genetic variants of TREM2 that are known to increase AD risk disrupt programmes predicted to control lipid metabolism and lysosomal protein degradation, while increasing expression of inflammatory mediators that may disrupt astrocyte functions. We further show that in astrocytes from human AD brain tissue (from Gabitto et al., 2024), programmes predicted to control protein synthesis and mitochondrial function are disrupted, which may impair metabolic support for neurons.

In conclusion, our work reveals transcriptional programmes predicted to control protective glial functions whose disruption may contribute to different steps of AD pathogenesis and suggests that TREM2 variants may increase AD risk by interfering with these programmes.