Cognitive and functional decline in Alzheimer’s disease (AD) follows a characteristic trajectory with specific onset, progression rate, and neuropathology (1). Alois Alzheimer first reported that extracellular plaques and intracellular neurofibrillary tangles (NFTs) comprise the main pathological hallmarks of AD in his 1907 paper (2). In recent years, human enzymes have been a focus of research across many scientific fields. Traditionally, AD is tackled with drugs like acetylcholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) (3–5) and the N-Methyl-D-Aspartate (NMDA) receptor allosteric modulator, memantine (6–8). Though these drugs have therapeutic effects, they also have significant drawbacks. According to a recent study that contrasts the former dogma, which believes that targeting Aβ would benefit the majority of AD patients, it is now believed that anti-Aβ monoclonal antibodies will not offer a magic bullet (9).

Consequently, there is a need to seek alternative treatments for AD, which is becoming more and more of a current focus. Medicinal herbs are both edible and medicinal (10, 11). Hence, they cause a substantial reduction in the side effects of medicines and drugs. On the other hand, most chemically synthesized drugs are designed to be single-target agents with a working hypothesis (12). As a result, if the hypothesis turns out to be false, the effectiveness of these drugs often falls apart. Unlike synthetic drugs, naturally made drugs act on multiple targets to give multiple effects. This ability to influence multiple targets makes them particularly useful for the treatment of diseases whose origins are not fully understood, like AD (13–17).

Polyphenols are organic compounds that can be natural, synthetic, or semi-synthetic, having more than one phenolic group (18). This means polyphenols usually consist of one or more aromatic rings with hydroxyl groups. Research shows that natural plant polyphenols have positive effects on human health over the years. The chemical composition of olive oil will depend on the extraction method used to obtain it from the fruit. Refined olive oils are devoid of vitamins, polyphenols, phytosterols, and other low-weight natural constituents. Unlike other varieties of olive oil, EVOO is more expensive due to its lower yield, but it contains the most polyphenols (19–22). The unique phenolic compounds present in olive oil, especially the phenolic alcohols hydroxytyrosol (3,4-DHPEA) and tyrosol (p-HPEA), as well as their respective secoiridoid derivatives, mainly 3,4-DHPEA-EA (oleuropein aglycon), p-HPEA-EA (ligstroside aglycon), 3,4-DHPEA-EDA, p-HPEA-EDA (oleocanthal), and oleuropein (23), have recently been attributed the chemopreventive potential of olive oil (Figure 1). The cancer-fighting ability of olive oil is connected to the antioxidant nature of its phenolic and polyphenolic constituents, which help in neutralizing free radicals and reactive oxygen species. The compounds oleuropein, tyrosol, hydroxytyrosol, verbascoside, ligustroside, and dimethyl europein protect against coronary artery disease (24–26) and cancer (27, 28). They also possess antimicrobial and antiviral properties (29, 30). The antioxidant and antiatherogenic effects of oleuropein and hydroxytyrosol (polyphenols from olive oil) are well established (31, 32).

Despite the established neuroprotective potential of individual EVOO polyphenols in preclinical models, a systematic review synthesizing their multi-target, synergistic mechanisms against the complex pathology of AD are lacking. This review aims to fill this gap by critically evaluating the mechanistic evidence for the most prominent EVOO polyphenols-hydroxytyrosol, oleuropein, tyrosol, verbascoside, oleocanthal, and ligustroside-in targeting key AD pathways, including Aβ and tau aggregation, neuroinflammation, oxidative stress, and mitochondrial dysfunction (Figure 2). Furthermore, we discuss the challenges in clinical translation and the relevance of existing human studies (see Table 1).

Hydroxytyrosol (HTyr) is the main phenolic molecule found in EVOO. It is a low molecular-weight phenotype with a catechol group. This chemical structure is responsible for its high bioactivity, which has antioxidant, cardioprotective, anticancer, anti-inflammatory, and notably neuroprotective effects (33–35).

HTyr is characterized by a catechol group that confers potent antioxidant, anti-inflammatory, and neuroprotective properties. The ability of HTyr to boost mitochondrial quality control is primarily responsible for its neuroprotective efficacy. It increases the nutritional absorption by improving its functionality in the intestine. It increases nitric oxide release, thereby improving blood flow to the digestive organs. It induces Epidermal Growth Factor (EGF) release and inhibits apoptosis. It also promotes cell proliferation through the epidermal growth factor receptor. The intracellular ATP levels are increased by HTyr and olive polyphenols in SH-SY5Y-APP695 cells (AD model) (36). In a similar vein, HTyr normalizes cerebral ATP production as well as enhances the activities of different electron transport chain components (NADH reductase, cytochrome c oxidase) and citrate synthase in 12-month-old mice with mitochondrial dysfunction. The metabolic recovery resulted in increased SIRT1 indications and concentration of CREB, Gap43 and GPX-1, which significantly improves spatial working memory (37).

HTyr worked positively on the hippocampal neurogenesis, thus preventing age decline in neurogenesis decline in case of neurodegenerative diseases. In adult, aged, and Btg1 knockout mice, HTyr treatment reduces apoptotic death of newborn neurons in the dentate gyrus, thus enhancing cell survival. According to (38), it also reduces markers of cellular senescence like lipofuscin aggregation and Iba1 immunoreactivity, proposing a role in the modulation of glial activation and oxidative stress. Another important mechanism is the inhibition of pathological protein aggregation. HTyr and oleuropein aglycone (OLE) inhibit Tau fibrillization, thereby reducing neurofibrillary tangle (NFT) formation and associated neuronal and glial pathology (39). HTyr metabolites also inhibit amyloid-β deposition in cellular models (40). In neuronal PC12 cells, these strong experiments reveal that HTyr suppresses the aberrant aggregation of α-synuclein, a protein that plays a key role in synucleinopathies. Also, it upregulates the deacetylase SIRT2, which possibly facilitates the clearance of misfolded proteins (41). These helpful benefits do result in cognitive improvement. Mice’s brain injections of Aβ1-42 caused loss of memory, but HTyr, in essence, helps mice to rescue their memory and control the apoptosis process (42). In APP/PS1 (Amyloid Precursor Protein/Presenilin 1) transgenic mice, a well-characterized transgenic model of AD, HTyr treatment improves performance in the Morris water maze test, reduces cortical and hippocampal apoptosis, and restores synaptic integrity (42).

HTyr confers neuroprotection through a multitude of actions, including improving mitochondrial function, enhancing neurogenesis, and inhibiting inflammation, apoptosis, and protein aggregation. It is ability to target multiple nodes of the neurodegenerative cascade underscores its potential as a polypharmacological agent for AD and other dementias.

Oleuropein (OLE) is the major phenolic found in olives. It is a kind of secoiridoid phenolic compound, which is made of three structural building blocks: HTyr, elenolic acid and glucose. It shows a wide variety of biological activities such as antioxidant, anti-hypertensive, and anti-inflammatory activities (43–46).

The neuroprotective effects of OLE are mediated through various mechanisms. The processes involve the induction of autophagy, activation of antioxidant capacity in various brain areas, and inhibition of neuroinflammation by inactivating microglia and astrocytes. Inactivation diminishes a greatly excessive release of pro-inflammatory mediators (47). It seems that people who eat OLE regularly have a lower risk of developing strokes, AD, Parkinson’s, and other neurological disorders. These advantages are supported by animal studies. Starting at 3 months of age, mice were fed a diet enriched in oleuropein (695 μg/kg b.w. per day) for 3 months. According to overall findings, OLE inhibits activation of the RAGE/HMGB1 pathway and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and NF-κB pathway, thus reducing neuroinflammation. Furthermore, OLE decreased total Aβ levels in the brain. This is due to enhanced clearance as well as decreased Aβ production along with superior blood-brain barrier (BBB) integrity and functioning. Due to these alterations, these improvements all lead to better memory performance (48). Supplementation of OLE (12.5 mg/kg/day) plus a polyphenol mixture improved cognitive capacity in transgenic (Tg) mice according to a different study (p < 0.0001). OLE significantly decreased cortical Aβ42 levels as well as areas and numbers of pyroglutamate-modified Aβ3–42 (pE-3Aβ), a highly pathogenic and aggregation-prone Aβ species (49).

A crucial element of OLE’s activity is its direct anti-aggregation action. The OLE aglycone exhibits multiple actions that counteracts the aggregation of the amyloid protein and mitigate its toxicity through various mechanisms; these include the processing of the amyloid precursor protein, the aggregation of the amyloid beta peptide and the tau, impaired autophagy, and neuroinflammation that have therapeutic effects in AD (21, 50–53). OLE, a phenolic compound found in extra virgin olive oil (EVOO), inhibits the toxicity and aggregation of Aβ42 in a rat model. The levels of soluble Aβ oligomers were significantly reduced as a result of OLE co-injection. Oleuropein prevents the cytotoxic effects of amyloid in cells when present (54). Analyses have shown that when amyloid aggregates form in the presence of oleuropein, they interact less with cell membranes as oleuropein alters the aggregation pathway away from the formation of toxic pre-fibrillar aggregates (55).

In transgenic Caenorhabditis elegans models of AD (CL2006 and CL4176), which express human Aβ and exhibit paralysis as a phenotypic readout, OLE treatment reduced Aβ deposition and delayed paralysis. In CL2006 worms, OLE treatment reduced Aβ deposition and oligomer form, delayed paralysis, and increased lifespan. The CL4176 worms only showed the protective effect of OLE when it was given before the induction of Aβ expression. These effects, which depend upon dose, do not seem (56). Moreover, OleA was also found to reduce cell toxicity by blocking the attachment of α-synuclein aggregates to cell membrane components, which cuts down on secondary oxidative damage to the cells (57). The OLE aglycone has anti-aggregation activity against the aggregation of both aggregation of Aβ42 and pE3-Aβ, together with reducing the expression of the enzyme, and interferes with pE3-Aβ formation due to glutaminyl cyclase. Furthermore, neuron autophagy was activated in the presence of this compound, which increased histone acetylation. This effect was related to downregulation of HDAC2, and a remarkable improvement in synaptic function was observed in mice showing advanced pathology (58). In another study, treatment of oleuropein (15 and 30 mg/kg) significantly improves spatial learning and memory in morphine given animals and reduces cell atrophy and oxidative stress in the hippocampus (59).

So, OLE and supplementing the diet can be a good promise to stop and/or slow the progression of AD. Oleuropein is a natural antioxidant compound that shows considerable neuroprotective potential. Preclinical evidence strongly suggests the ability of OLE to combat certain chalk marks of AD, PD, and other similar-related ailments, improving cognitive activity and synaptic function. The findings demonstrate oleuropein’s potential as a valuable candidate for further translational research and dietary intervention strategies to slow down the progression of neurodegenerative diseases.

Tyrosol is a bioactive phenolic compound found in high concentrations in natural products such as olive oil and wine. It has a large variety of biological functions that include antioxidant, anti-inflammatory, cardioprotective, and neuroprotective effects (60–62). Increasing evidence from preclinical studies suggests that it may help in preventing neurodegenerative pathology.

Animal studies have shown that treatment with tyrosol significantly improves cognitive deficits in vivo. In the hippocampus, tyrosol reduced oxidative stress markers (ROS and MDA) and enhanced activities of antioxidant enzymes (GPX and SOD) in PMD rats. Further, concentrations of brain-derived neurotrophic factor (BDNF) and monoamine neurotransmitters (5-HT, DA, and NE) were significantly increased here (63). In AD models, a study reported that oral tyrosol decreased spatial memory impairment as measured by the Barnes maze test and decreased oxidative damage in the CA3 region of the hippocampus, a subregion critical for spatial memory and learning (64). Tyrosol has significant anti-amyloidogenic properties at the molecular level. Key contributors to AD pathogenesis, soluble Aβ oligomers, trigger toxicity to cells and synapses. Primary neurons showed a significant inhibition of caspase-3 by tyrosol induced by Aβ Oligomers (AβO). Co-treatment with tyrosol or its metabolite HTyr resulted in the decrease of Aβ-induced cytotoxicity in neuroblastoma N2a cells (65). These results demonstrate that tyrosol protects against Aβ toxicity by counteracting oxidative stress and modulating inflammation.

Notably, extracts rich in tyrosol show strong neuroprotective efficacy. Rhodiola sachalinensis, which is rich in tyrosol, improved cognitive performance in scopolamine-induced amnesia models. Taking R. sachalinensis improved performance in Y-maze, passive avoidance, and water maze tests. This was also accompanied by reduced activity of acetylcholinesterase, increased activity of antioxidant enzymes (SOD and CAT), and downregulation of the expression of Aβ_₁–₄₂ and APP (66).

Together, these studies suggest that tyrosol protects the brain through many different effects, including reducing oxidative stress, boosting brain cell growth signals, protecting against Aβ damage, and controlling cell death and inflammation. Increasing evidence from preclinical studies suggests that it may help in preventing neurodegenerative pathology.

Verbascoside (VB) has emerged as a promising neuroprotective agent in experimental models of AD, demonstrating multiple mechanisms countering key pathological processes, including neuroinflammation, oxidative stress, synaptic dysfunction, and protein misfolding (67, 68).

One of the mechanisms through which VB exerts its beneficial effects is the modulation of neuroimmune response. Under APP/PS1 transgenic mice (the most popular Alzheimer’s disease model), the treatment with VB drastically inhibited the activation of microglia and astrocytes. This induced a shift from the pro-inflammatory M1 phenotype, as indicated by decreased expression of CD11b, iNOS, and IL-1β, to the anti-inflammatory M2 phenotype, as indicated by increased levels of Arg-1 and TGF-β1. This shift is largely mediated by suppression of the NF-κB signaling pathway. The administration of VB significantly decreased the phosphorylation levels of IKKα and IKKβ, IκBα, and NF-κB-p65. Furthermore, VB reduced the nuclear translocation of NF-κB-p65 in vivo and in vitro. This suggests that VB has a potent anti-inflammatory activity (67, 69).

At the same time, VB treatment significantly improves cognitive performance and pathology. In rodent models like APP/PS1 and D-galactose/AlCl3-induced aging mice, VB improved learning and memory functions. According to Morris water maze and step-down tests, VB reduced escape latency, increased the number of platform crossings, and decreased errors (70, 71). VB reduced the deposition of Aβ plaques and attenuated the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, which happens due to neuronal atrophy. Also, correlation of structural, biochemical functional benefits was noted. Also, correlation of structural biochemical functional benefits was noted. These happened due to neuronal atrophy and enhanced density of Nissl bodies and neurons of the hippocampus (70, 72). Moreover, VB was found to suppress 4-hydroxynonenal biomarkers and caspase-3 activity (70, 72). Subsequently, these findings indicate that VB downregulated apoptosis. At the cell level, VB protected against toxicity from Aβ. In U251 and PC12 cells damaged by Aβ_₁–₄₂, VB improved cell viability, suppressed apoptosis, inhibited cytosolic calcium accumulation and reactive oxygen species, and modified mitochondrial and endoplasmic reticulum (72, 73). Additionally, VB also changed synaptic function by inducing extracellular Ca²⁺ influx through L-type voltage-gated channels that activated the CaMKII pathway, upregulated synaptic vesicle-associated proteins and inhibited the activity of acetylcholinesterase (73). Aside from these mechanisms, VB and its esterified derivative verbascoside penta propionate (VPP) inhibit Aβ aggregation dynamics and its cytotoxicity with no metal ion, indicating the involvement of another mechanism in its neuroprotection profile (74).

Taken together, the evidence from experiments points to VB being a multi-target neuroprotective agent that acts effectively in diverse AD models. VB is a huge neuroinflammatory agent. It significantly reduces the activity of microglia and astrocytes at a cellular level. There is a change from M1 to M2, which means from an inflammatory to an anti-inflammatory environment. It accomplishes this through reduction of the NF-κB signaling pathway. At the same time, VB improves cognitive impairments and decreases characteristic illnesses of the nervous system, including Aβ deposition, tau hyperphosphorylation, and damage caused by oxidative stress. Also, it enhances neuronal resilience by reducing apoptosis, stabilizing calcium homeostasis, and preserving mitochondrial integrity while benefiting synaptic function through Ca²⁺-mediated signaling and cholinergic boosting. Finally, VB and VPP inhibit Aβ aggregation, complementing the metal ion-binding mechanism, through their direct action against Aβ. Together, these attributes position VB as a promising multifaceted candidate for slowing AD progression.

The presence of oleocanthal and ligustroside in extra virgin olive oil (EVOO) is increasingly being studied for their neuroprotective effects in the model of Alzheimer’s disease (AD). The OC has been developed quite well in many experimental systems. But ligustroside is a candidate that has promise, but has not yet been evaluated.

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.

The multifaceted pathology of Alzheimer’s disease necessitates a shift from single-target to multi-target therapeutic strategies. As detailed in this review, extra virgin olive oil polyphenols—including hydroxytyrosol, oleuropein, tyrosol, verbascoside, oleocanthal, and ligustroside—exert synergistic neuroprotection by concurrently modulating a network of key AD-related pathways. Their ability to inhibit Aβ and tau aggregation, enhance Aβ clearance, suppress chronic neuroinflammation, restore mitochondrial and metabolic function, reduce oxidative stress, and promote neurogenesis and synaptic plasticity underscores their significant potential. While challenges in clinical translation remain, the compelling preclinical evidence, coupled with the safety and dietary relevance of EVOO, positions these natural compounds as promising candidates for integrative approaches to delay the onset and slow the progression of AD. Future research should focus on validating these benefits in human trials and developing optimized formulations for clinical application.