PPARγ at the Nexus of Lipid Metabolism and Neuroinflammation in Alzheimer's Disease: A Longitudinal Multi-omics Analysis.

Peroxisome proliferator-activated receptor gamma (PPARγ) has emerged as an important regulator linking lipid metabolism and neuroimmune responses in Alzheimer's disease (AD). Increasing evidence suggests that disruption of the lipid-immune axis contributes to disease progression and may underlie the heterogeneous therapeutic responses observed with PPARγ-targeted interventions. Experimental studies indicate that PPARγ activation influences multiple biological processes relevant to AD, including lipid homeostasis, mitochondrial function, inflammatory signaling, and amyloid-β clearance. However, the translation of these findings into consistent clinical benefit remains limited by challenges such as poor blood-brain barrier penetration, systemic adverse effects, and disease stage-dependent therapeutic responses. Recent advances in multi-omics technologies and single-cell transcriptomics have provided new insights into the context-dependent roles of PPARγ in different neural cell populations, highlighting dynamic interactions between lipid metabolism, neuroinflammation, and cellular function throughout AD progression. These findings suggest that PPARγ-associated pathways may represent an important regulatory interface linking metabolic and inflammatory processes, while emphasizing the complexity of their temporal and cell-specific regulation. This review synthesizes current evidence from experimental studies, human multi-omics investigations, and clinical research to provide an updated perspective on the role of PPARγ in coordinating lipid metabolism and neuroinflammation in AD. In addition, we discuss the major translational challenges and emerging therapeutic strategies, including selective PPARγ modulation, improved central nervous system delivery, and precision treatment approaches tailored to disease stage.