Background: Microglia, the resident macrophages of the brain, play critical roles in both normal brain development and the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD). Despite their recognised importance, the precise contributions of microglia to AD pathology are not yet fully understood.

Methods: To investigate the role of microglia in development and AD, we used a genetically engineered microglia-deficient mouse model (Csf1r∆FIRE/∆FIRE). Single-cell and single-nucleus transcriptomic analyses of neurons and astrocytes in the cerebral neocortex were performed to assess transcriptional changes in the absence of microglia (sex-balanced, n=4 per genotype for scRNA-seq;n=6 per genotype for snRNA-seq). To explore microglial involvement in amyloid pathology, we generated a combined microglia-deficient amyloidosis model (Csf1r∆FIRE/∆FIRE x APPSwe/PS1dE9 (APP/PS1);mixed gender, n=5–7 per genotype) and applied multi-omics approaches, including sc/snRNA-seq, spatial transcriptomics, and protein analysis.

Results: In early development, the absence of microglia did not produce major transcriptional disturbances in neurons or astrocytes, suggesting these programmes can establish largely independently of microglia. In the amyloidosis model, microglia deficiency led to a significant reduction in amyloid plaque burden and cortical inflammatory gene expression, supporting a detrimental role of microglia in plaque pathogenesis. Nonetheless, other pathological features—including plaque-proximal astrogliosis, synapse loss, and neuritic dystrophy—were persisted in the absence of microglia.