Effects of PPAR Modulation on Cognitive Function and Oxidative Stress in Experimental Alzheimer's Disease: A...

Oxidative stress is a key pathological feature of Alzheimer's disease (AD), characterized by increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), 4-hydroxynonenal, and protein carbonyls, alongside impaired antioxidant defenses such as superoxide dismutase (SOD). These alterations contribute to endoplasmic reticulum stress, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and cognitive decline. Peroxisome proliferator-activated receptors (PPARs) have been recognized for their antioxidant, anti-inflammatory, and neuroprotective properties; however, their effects on oxidative stress in AD have not been systematically evaluated. A systematic review and meta-analysis were conducted using PubMed, Scopus, and Web of Science, with an updated search performed in February 2026. Twenty-nine eligible studies were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for outcomes reported in at least three studies. Heterogeneity was assessed using Cochran's Q and I² statistics, and random-effects models were applied when necessary. PPAR agonists significantly improved cognitive performance in the Morris water maze, reducing escape latency (p = 0.02). Protein and gene expression levels of PPARs were significantly increased compared to controls (p < 0.001). Experimental studies showed enhanced antioxidant capacity, including increased SOD levels and reduced MDA and ROS production. PPAR activation also decreased BAX expression, suggesting reduced apoptosis and improved cell viability. In addition, PPAR agonists attenuated amyloid-β deposition and improved neuronal morphology, whereas receptor antagonists largely reversed these beneficial effects. Current preclinical evidence suggests that PPAR modulation exerts beneficial effects on cognition, oxidative stress, and neuroinflammatory pathways in experimental AD. Nevertheless, substantial methodological heterogeneity and the absence of clinical evidence warrant cautious interpretation and further translational studies.