Peroxisomes in Alzheimer’s disease: emerging mechanistic insights and therapeutic opportunities

Abstract

Alzheimer’s disease (AD) is characterized by amyloid- β (Aβ) deposition, tau pathology, synaptic injury, neuroinflammation, oxidative stress, and disrupted organellar homeostasis. Peroxisomes maintain lipid and redox balance through very-long-chain fatty acid (VLCFA) β -oxidation, plasmalogen biosynthesis, and reactive oxygen species (ROS) metabolism. This Review evaluates how peroxisomal alterations may modulate APP processing and Aβ clearance, tau kinase/phosphatase balance, neuroinflammation, oxidative stress, and peroxisome-mitochondria crosstalk. We distinguish human correlational evidence from intervention studies in AD models and mechanistic extrapolation from primary peroxisomal disorders. Current evidence supports a context-dependent vulnerability or amplifier model rather than a universal causal pathway. Peroxisome-targeted interventions remain investigational, and no validated biomarker currently identifies an AD subgroup for such treatment.