Olive Components (Biophenols or Polyphenols) in Neurodegenerative Disease Models and Clinical Studies: A Systematic Review of Evidence and Translational Barriers

Introduction: Olives have been used in traditional Mediterranean medicine for thousands of years to address the causes of inflammation, ageing and cognitive health. Traditional preparations of olive include olive oil and olive leaf extract, which are major components of diets that contribute to maintaining cognitive function and reducing neurodegenerative disease risk. Aims of the study: This systematic review aimed to synthesise experimental and limited human evidence on olive biophenols in neurodegenerative disease models, identify the most studied compounds, characterise their mechanisms of action, and evaluate key translational barriers. Materials and methods: Following PRISMA 2020 guidelines and registered with PROSPERO (CRD420251252252), primary studies investigating the effects of well-characterised olive biophenols in neurodegenerative relevant in vitro, in vivo, or human models were systematically reviewed. Each study was assessed for its design, experimental model, mechanistic outcomes and reported limitations. Risk of bias was evaluated using validated tools (SYRCLE/OHAT/ToxR) appropriate for preclinical and experimental study designs. Results: Among the 25 studies, 7 (28.0%) examined oleuropein or oleuropein aglycone, 10 (40.0%) focused on hydroxytyrosol or its derivatives, and 9 (36.0%) investigated oleocanthal. Most studies employed in vivo animal models (57.7%), predominantly transgenic mouse models of AD and toxin-induced PD models. Oleuropein-based studies reported inhibition of amyloid-β and α-synuclein aggregation with behavioural improvements. Hydroxytyrosol primarily exerted antioxidant and anti-inflammatory effects with modest cognitive benefits. Oleocanthal showed the most consistent anti-amyloid and anti-tau activity, including enhanced amyloid-β clearance across the blood–brain barrier. Most studies show a moderate risk of bias due to incomplete reporting, randomisation and blinding. Conclusions: Olive biophenols demonstrate consistent neuroprotective effects in preclinical models; however, translation to clinical application remains limited by pharmacokinetic constraints, methodological heterogeneity, and insufficient human evidence.