Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and lipid metabolic dysfunction, with disease-associated microglia (DAM) playing a central role in disease progression. We investigated microglia-specific transcriptional alterations in AD, focusing on the FOXO1–PPARγ regulatory axis. Single-nucleus RNA-sequencing data (GSE174367; 61,472 nuclei, including 4,126 microglia) were analyzed using Seurat. FOXO1 expression was significantly decreased, whereas PPARγ expression was significantly increased in AD microglia, particularly within DAM, compared with controls (p < 0.001). Across amyloid plaque stages, FOXO1 progressively declined while PPARγ increased significantly. Phagocytosis-related genes displayed stage-dependent changes, with early upregulation followed by significant downregulation during advanced disease. These findings suggest that suppression of FOXO1 coupled with sustained PPARγ activation disrupts lipid homeostasis and progressively impairs microglial phagocytic function during AD progression. The FOXO1–PPARγ axis may represent a key regulator of microglial dysfunction and a potential therapeutic target in AD.