In this review, we have summarized the efficacious roles of various EVOO polyphenols against the pathological processes of AD

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 16 times in total.

Supporting evidence — 3 representative gaps

• Multitarget Actions of Pentacyclic Triterpenic Acids in Alzheimer’s Disease: Mechanistic Insights (2026) · Molecules · doi

  AD remained a complex neurodegenerative disorder with limited disease-modifying therapies. This review summarized the neuroprotective effects of PTAs, including AA, BTA, BA, GA, MA, OA, and UA, which demonstrated antioxidant, anti-inflammatory, anti- amyloidogenic, mitochondrial-protective, and synaptic regulatory properties in cellular and animal models of AD. Several PTAs also improved learning and memory in behavioral https://doi.org/10.3390/molecules31122018 Molecules 2026, 31, 2018 20 of 29 studies, highlighting their multitarget therapeutic potential. However, most evidence remains preclinical, and the reported benefits were largely derived from in vitro systems or rodent models that may not fully represent the complexity of human AD. Clinical evidence is still limited to a few small-scale studies with short follow-up periods and insufficient validation using established AD biomarkers or neuroimaging approaches. In addition, poor solubility, limited oral bioavailability, uncertain BBB penetrations, and incomplete pharmacokinetic characterization continue to restrict the translational applicability of many PTAs. Several compounds, including CA, MAA, and ARA, also lacked direct evaluations in AD-specific models, despite showing neuroprotective effects in other neurological conditions. Future research should, therefore, focus on rigorous mechanistic studies, standardized dose-response evaluations, long-term safety assessments, and well-designed clinical trials. Improving delivery strategies through nanoformulations, structural modification, or intranasal administration may further enhance therapeutic effi- cacy while reducing systemic limitations. Delivery systems, such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, and nanoemulsions, were potential in improving the solubility, stability, and CNS delivery of several PTAs, particularly GA. Overall, PTAs represented an interesting source of multitarget neuroprotective com- pounds, but substantial experimental and clinical validation was still required before their utility in AD therapy can be established. Author Contributions: Conceptualization, N.S. and S.S.A.A.; writing—original draft preparation, N.S.; writing—review and editing, N.S. and S.S.A.A.; funding acquisition, S.S.A.A. All authors have read and agreed to the published version of the manuscript. Funding: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (Grant number RS-2021- NR060117), and by the Korea Institute of Marine Science & Technology Promotion (KIMST), funded by the Ministry of Oceans and Fisheries (Grant number RS-2025-02292973). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The original contributions presented in this study were included in the article. Acknowledgments: Grammarly (https://www.grammarly.com/, accessed on 24 May 2026) was used for language editing to improve readability. Chemical structures were prepared using RCB PDB. Figures were created in Biorender. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: ptas limited review neuroprotective models several clinical delivery statement effects including anti https molecules multitarget
• Neuroprotective properties of extra virgin olive oil polyphenols in Alzheimer’s disease: a multi-target mechanistic review (2025) · Frontiers in Nutrition · cited 6× · doi

  In this review, we have summarized the efficacious roles of various EVOO polyphenols against the pathological processes of AD. These compounds target multiple fronts: hydroxytyrosol and oleuropein inhibit the aggregation of Aβ and tau; oleocanthal promotes Aβ clearance across the BBB; verbascoside and oleocanthal suppress neuroinflammation via NF-κB and NLRP3; hydroxytyrosol and others restore mitochondrial homeostasis and reduce oxidative stress; and several compounds promote neuroplasticity and synaptic function. Despite compelling preclinical evidence, the translation of EVOO polyphenols into validated combinatorial therapies or preventive strategies for AD faces significant challenges. A major hurdle is the gap between animal models and human AD, particularly regarding disease complexity, progression, and species differences in metabolism and pharmacology. While epidemiological studies, such as those on the Mediterranean diet, suggest cognitive benefits, well-designed, large-scale, long-term human intervention trials specifically targeting EVOO polyphenols in AD prevention and management are still limited. Future clinical research must address critical questions regarding optimal dosing, formulation for enhanced bioavailability, treatment duration, and the identification of specific patient populations most likely to benefit. Furthermore, the synergistic effects of the EVOO polyphenol complex, as opposed to isolated compounds, need rigorous evaluation in humans. The safety profile of EVOO is excellent, which facilitates its consideration for long-term use; however, standardized extracts with defined polyphenol content are necessary for reproducible clinical outcomes. In recent years, the impact of diet on human health has become a major research focus. Individuals are increasingly seeking simple, dietary means to prevent disease or support health. EVOO, a staple of the Mediterranean diet rich in natural polyphenols, is well-positioned to play an important role in this context. Future research should prioritize human studies that integrate biomarkers of AD pathology, neuroimaging, and cognitive assessments to firmly establish the role of EVOO and its bioactive polyphenols in combating Alzheimer’s disease.

  generalfuture work
  Keywords: evoo polyphenols human compounds disease diet hydroxytyrosol oleocanthal major regarding mediterranean cognitive well long term
• Potential Neuroprotective Effects of Alpinia officinarum Hance (Galangal): A Review (2024) · Nutrients · cited 10× · doi

  Taken together, this review provided important insights into the therapeutic potential of A. officinarum and its bioactive compounds in the treatment of neurological disorders. Several studies on A. officinarum and its bioactive compounds show its pharmacological ac- tivities in a number of neurological disorders. Despite the widespread use of A. officinarum extract and its bioactive compounds in various models of neurological disorders, the actual mechanisms underlying the therapeutic effects are known to be diverse but poorly under- stood. Some studies have found considerable therapeutic effects in in vitro studies, but the evidence from in vitro studies needs to be confirmed in in vivo studies. For example, in vitro studies suggest that A. officinarum extract and its diarylheptanoids can treat and pre- vent AD through various mechanisms such as antioxidation, anti-apoptosis, anti-amyloid and anticholinesterase. However, further studies on brain tissue and cognitive function in animal models of AD should be conducted to confirm the claims described. Although A. officinarum extract has been reported to improve memory impairments in the PTZ seizure rat model, further studies on the effects of A. officinarum on cognition should be conducted using different protocols involving all forms of memory, such as the Morris water maze, Nutrients 2024, 16, 3378 18 of 24 open-field test, T-maze and radial arm maze, to identify the specific cognitive areas that respond best to A. officinarum. To validate the effect of A. officinarum on memory restora- tion, further experiments are needed to measure the levels of neurotransmitters (such as acetylcholine and dopamine) and neurotrophic factors (such as nerve growth factor-NGF and brain-derived neurotrophic factor) involved in learning and memory functions and to assess long-term potentiation (LTP) in the hippocampal regions. In addition, further experiments should be conducted to prove that A. officinarum is a potential herbal medicine for AD by evaluating its effect in attenuating the accumulation of Aβ and phosphorylated tau protein in AD brain tissue. A. officinarum has also been shown to attenuate the biological hallmark of PD by inhibiting α-synuclein aggregation. However, future studies are needed to evaluate the motor functions, neurochemical changes and pathological changes associated with PD in an in vivo model. Despite the promising neuroprotective properties of A. officinarum reported in previous studies, it is unclear how A. officinarum reaches and specifically acts on neural cells. Therefore, it is important to investigate the ability of A. officinarum to cross the BBB and its affinity for CNS receptors to gain a better understanding of its efficacy as a therapeutic agent in CNS disorders. There is also a lack of human clinical trials to confirm the safety and efficacy of A. officinarum in neurological disorders. Future studies need to include a comprehensive assessment of adverse effects, inve

  generalfuture work
  Keywords: officinarum disorders therapeutic neurological effects further memory bioactive compounds extract vitro brain conducted maze important

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