Olive Leaf Extracts With High, Medium, or Low Bioactive Compounds Content Differentially Modulate Alzheimer's Disease via Redox Biology

ABSTRACT Alzheimer's disease (AD) involves β‐amyloid plaques and tau hyperphosphorylation, driven by oxidative stress and neuroinflammation. Cyclooxygenase‐2 (COX‐2) and acetylcholinesterase (AChE) activities exacerbate AD pathology. Olive leaf (OL) extracts, rich in bioactive compounds, offer potential therapeutic benefits. This study aimed to assess the anti‐inflammatory, anti‐cholinergic, and antioxidant effects of three OL extracts (low, mid, and high bioactive content) in vitro and their protective effects against AD‐related proteinopathies in Caenorhabditis elegans models. OL extracts were characterized for phenolic composition, AChE and COX‐2 inhibition, as well as antioxidant capacity. Their effects on intracellular and mitochondrial reactive oxygen species (ROS) were tested in C. elegans models expressing human Aβ and tau proteins. Gene expression analyses examined transcription factors (DAF‐16, skinhead [SKN]‐1) and their targets (superoxide dismutase [SOD]‐2, SOD‐3, GST‐4, and heat shock protein [HSP]‐16.2). High‐OL extract demonstrated superior AChE and COX‐2 inhibition and antioxidant capacity. Low‐ and high‐OL extracts reduced Aβ aggregation, ROS levels, and proteotoxicity via SKN‐1/NRF‐2 and DAF‐16/FOXO pathways, whereas mid‐OL showed moderate effects through proteostasis modulation. In tau models, low‐ and high‐OL extracts mitigated mitochondrial ROS levels via SOD‐2 but had limited effects on intracellular ROS levels. High‐OL extract also increased GST‐4 levels, whereas low and mid extracts enhanced GST‐4 levels. OL extracts protect against AD‐related proteinopathies by modulating oxidative stress, inflammation, and proteostasis. High‐OL extract showed the most promise for nutraceutical development due to its robust phenolic profile and activation of key antioxidant pathways. Further research is needed to confirm long‐term efficacy.