{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:09:01Z","timestamp":1788775741357,"version":"build-2803163510"},"reference-count":161,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent\/metabolite pharmacokinetics, blood\u2013brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2\/antioxidant response element (Nrf2\/ARE) activation and experimental modulation of \u03b1-synuclein; support for AMP-activated protein kinase (AMPK)\/sirtuin 1 (SIRT1)\/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1\u03b1), mitochondrial protection, nuclear factor-kappa B (NF-\u03baB)-related inflammation, and amyloid-\u03b2 (A\u03b2) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin\u2013proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose\u2013response, and efficacy require adequately powered disease-specific trials.<\/jats:p>","DOI":"10.3390\/molecules31173113","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:23:37Z","timestamp":1788773017000},"page":"3113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydroxytyrosol as a Multitarget Neuroprotective Agent: Molecular Mechanisms, Pharmacokinetics and Therapeutic Potential in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7345-448X","authenticated-orcid":false,"given":"Pura","family":"Ballester-Navarro","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Nutrition, UCAM Universidad Cat\u00f3lica de Murcia, 30107 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1021-5385","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"Garc\u00eda-Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Nutrition, UCAM Universidad Cat\u00f3lica de Murcia, 30107 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-9477","authenticated-orcid":false,"given":"Desir\u00e9e","family":"Victoria-Montesinos","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Nutrition, UCAM Universidad Cat\u00f3lica de Murcia, 30107 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-7120","authenticated-orcid":false,"given":"Pilar","family":"Zafrilla","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Nutrition, UCAM Universidad Cat\u00f3lica de Murcia, 30107 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/S1474-4422(24)00038-3","article-title":"Global, Regional, and National Burden of Disorders Affecting the Nervous System, 1990\u20132021: A Systematic Analysis for the Global Burden of Disease Study 2021","volume":"23","author":"Steinmetz","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhu, X., Yu, J., Lai, X., Wang, X., Deng, J., Long, Y., and Li, B. 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