1. Introduction

2. Hydroxytyrosol safety and common doses of dietary origin and in functional foods

Table 1. Dose conversion factors of HT doses between rats and humans.

3. Pre-clinical evidence of the role of hydroxytyrosol and derivatives in neuroprotection

3.2. Animal in vivo studies

In the last decade, there has been an increase in the number of animal studies evaluating the neuroprotective effects of EVOO phenolic compounds, with a focus on the possible modulation of the distinctive features of brain degeneration.

3.2.1. Capacity to cross the BBB:

Animal studies have provided evidence that EVOO phenolic compounds are capable of crossing the BBB, allowing them to potentially exert their beneficial biological activities in the brain. Following the administration of an HT nutritionally relevant dose, HT metabolites were detected in the brain tissue (25). HT specifically was measured in rat brain after 5 min of intravenous injection (1.5 mg/kg), the brain tissue containing 0.31% of the administrated dose (48). An interesting study described that HT preferentially accumulated in the hippocampus (49), a key site for spatial learning, memory, and emotional management, one of the brain regions most damaged in the development of depression (50). Additionally, it was demonstrated that the uptake of HT in the brain of rats was much higher in a pathological state, due to the increased BBB permeability (49), a common feature in several neurological diseases (51).

Table 2. Effects of HT and derivatives in in vitro neurodegenerative and Parkinson’s disease models.

Table 2. Effects of HT and derivatives in in vitro neurodegenerative and Parkinson’s disease models.

Study	In vitro model	Compounds tested	Concentrations	Significant outcomes	Ref.
Yu et al. 2016	SH-SY5Y cells treated with 6-OHDA	HT	20 – 90 µM	Induction of the expression of phase II detoxifying enzymes NQO1, GST, GCL and HO-1	(36)
Crespo et al., 2017	Astrocytic cell line C6 exposed to Aβ (25-35)	HT	5 µM	Prevention of viability decrease through increased Akt activation.	(44)
Omar et al., 2017	SH-SY5Y cells treated with copper and H2O2	HT	10 – 50 μM	Antiradical and protective activity against peroxidation	(34)
Funakohi-Tago et al., 2018	SH-SY5Y cells treated with 6-OHDA	HT, HT acetate and HT butyrate	5 – 10 µM	Reduction of the 6-OHDA-induced generation of ROS, activation of caspase-3, and subsequent cell death by HT butyrate, but not HT or HT acetate. HT butyrate induced Nrf2 and HO-1 expression	(35)
Hornedo-Ortega et al., 2018	Rat pheochromocytoma PC12 cells	HT	25 – 200 µM	Inhibition of α-synuclein fibrils formation and of their pro-inflammatory activity.	(46)
Lopez de Las Hazas et al., 2018	Neuroblastoma SH-SY5Y and neuronal-like LUHMES cells	HT, HT acetate, HT sulphate, HT acetate-sulphate	2.5 – 10 μM	Neuroprotection after oxidative injury observed after the pre-incubation with HT acetate. HT > HT acetate/sulphate.	(26)
Gallardo-Fernández et al., 2019	Murine microglial BV2 cells	HT	1 - 50 µM	Inhibition of α-synuclein aggregation and of NF-ĸB activation.	(45)
Leri et al., 2019	SH-SY5Y cells treated with Aβ1-42 oligomers	HT and oleuropein	0 - 20 µM	HT in synergy with oleuropein activated the autophagic flux in order to prevent cell damage. HT alone accelerated the formation of harmless fibrils to the detriment of harmful ones.	(41)
Hsu et al., 2021	Human cortical neuronal HCN-2 cells treated with rotenone	HT	30 μM	Inhibition of rotenone-induced cytotoxic responses by limiting Ca2+ entry. Treatment with HT reversed ROS levels, cytotoxic responses, and antioxidant enzyme activities (SOD, GPX and CAT) in rotenone-treated cells.	(39)
Mursaleen et al., 2021	hCMEC/D3-SH-SY5Y cell co-culture treated with rotenone	HT delivered through nanoformulations	20 - 200 µM	Encapsulation increased HT-induced protection against rotenone cytotoxicity and oxidative stress.	(40)
Visioli et al., 2022	7PA2 cell line transfected with cDNA encoding human amyloid precursor protein APP751	HT	5 µM	Increase of new mitochondria at 8 h post-HT treatment, followed by higher mitochondrial fusion and increased ATP concentrations after 24 h of treatment with HT with respect to the untreated cells.	(47)
Nardi et al., 2023	SH-SY5Y cells treated with 6-OHDA	HT and derivatives esterified and encapsulated in nanoformulations	0.005 – 0.1 μM	Antioxidant capacity of the compounds tested. Better efficacy was observed after encapsulation.	(38)
Rivero-Pino et al., 2023	Human peripheral blood mononuclear cells treated with Aβ1-42 oligomers	HT	41 µM	Down-regulation of pro-inflammatory cytokine gene expression and of neutrophil activation.	(43)

6-hydroxydopamine (6-OHDA), amyloid β1-42 (Aβ1-42), catalase (CAT), glutamate–cysteine ligase (GCL), glutathione peroxidase (GPX), glutathione-S-transferase (GST), heme-oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor ĸB (NF-ĸB), reactive oxygen species (ROS), superoxide dismutase (SOD).

3.2.2. Modulation of oxidation/inflammatory pathways:

Based on the in vitro capacity of olive oil phenolic compounds to modulate oxidative stress and inflammation, these pathways have been widely studied in animal models to elucidate the biological mechanisms of EVOO phenols to protect the aging brain (Table 3). These two pathways are key in the pathogenesis of neurodegeneratives diseases such as AD and PD.

In transgenic APP/PS1 mice, HT (5 mg/kg/day) modulated mitochondrial oxidative dysfunction, as indicated by the reduction of mitochondrial carbonyl proteins and GSSG, the increased SOD expression, and the restoration of phase II enzymes expression (52). HT intervention also reduced the levels of brain pro-inflammatory factors (IL-18, IL-6, and COX-2), which are induced in AD mice through the modulation of MAPK signalling pathways (52,53). Supplementation with HT (at a single dose of 70 mg/kg) in a depressive mouse model alleviated depression-like behaviours through the modulation of fatty acids metabolism in the hippocampus and inhibited microglia activation (49). In the same model, HT (50 mg/Kg) ameliorated oxidative stress in the hippocampus by enhancing SOD activity and reducing ROS and malondialdehyde (MDA) levels. HT also exerted anti-inflammatory effects, inhibiting TNFα and IL-1β expression, and upregulated the levels of brain-derived neurotrophic factors (54,55). Lipopolysaccharides (LPS) are widely used to induce a strong pro-inflammatory response. HT treatment (100 mg/kg) in mice subjected to systemic injection of LPS strongly inhibited the increased expression of proinflammatory mediators (TNF-α, IL-6, IL-1β, iNOS, and COX-2) induced in the brain, hence modulating neuroinflammation (56). Improvements in cognition were observed in APP/PS1 AD mice fed with HT acetate (50 mg/kg/day), by ameliorating electrophysiological dysfunction of neurons and brain inflammation through the modulation of NF-𝜅B activity and MAPK signalling (57). HT-acetate effectively protected neurons from inflammation and apoptosis in AD mice by enhancing the transcription of mitochondrial ER𝛽, whose expression in frontal cortex neurons is significantly decreased in AD patients (57). HT also improved mitochondrial function and prevented oxidative stress by activating the SIRT1/AMPK/PGC1 axis in the brain of db/db mice, a model of type 2 diabetes (58), whose unregulated glucose metabolism is related to AD onset (59).

MAO (monoamine oxidase) is an enzyme involved in breaking down neurotransmitters, and it is implicated in the pathogenesis of neurodegenerative diseases. Increased MAO activity is linked to decreased dopamine levels in PD and is thought to contribute to the formation of amyloid beta plaques in AD. MAO has also been shown to generate ROS, triggering oxidative stress and contributing to neurodegeneration (60). In vivo, evidence of the neuroprotective effect of HT has recently been provided also in an MPP+ model of PD in rats. A single intravenous administration of 1.5 mg/Kg of HT before intrastriatal infusion of MPP+ led to a significant reduction of the number of ipsilateral rotations, correlated with the preservation of striatal dopamine levels, due to the inhibitory effect of HT on MAO isoforms activity (61,62). In the same model, pre-treatment of rats with HT and its derivatives, HT acetate, and nitro-HT, protected them from dopamine neuron degeneration, restoring MPP+-induced redox unbalance, as shown by the decrease of lipid peroxidation products and the rise of GSH/GSSG ratio (glutathione/glutathione disulphide), giving further evidence of the main role of HT antioxidant action in neuroprotection (62). A selective MAO-B inhibitory ability of HT was reported in a PD mice model, where HT (50 mg/kg) restored dopamine levels in the brain, prevented loss of dopaminergic neurons in the substantia nigra and striatum and improved behavioural deficits (63).

3.2.3. HT in the prevention of neuronal loss:

Neurodegeneration is a complex process characterized by the progressive loss of neuronal function and structure. In vivo evidence of the ability of HT to improve neurogenesis, counteracting its physiological decline during aging, has been provided in a mice model of accelerated neural aging (Table 3). HT treatment (100 mg/kg/day) activated neurogenesis in the dentate gyrus, increased survival of new neurons, and decreased apoptosis (64). Studies in AD mice also highlighted the ability of HT to enhance the survival of neurons inhibiting cerebral cortex apoptotic responses by suppressing the mitochondria-mediated apoptotic pathway (52,53). In a mouse model, HT (45 mg/Kg/day) facilitated recovery after ischemic stroke by ameliorating stroke-associated learning and motor impairments. This was achieved through an increase in cerebral blood flow, functional and structural connectivity, and anti-inflammatory and neurogenic activity (65). Notably, Arunsundar et al. also demonstrated that HT restored the expression of genes involved in the regulation of survival and memory functions: SIRT1 (sirtuin1; NAD+-dependent deacetylase), CREB, and CREB target genes that regulate cognitive functions and ADAM10, a SIRT1-regulated metalloprotease down-regulated in AD (53).

3.2.4. Modulation of cognition

The ability of HT to enhance cognitive performance in various animal models of age-related diseases and neurological dysfunctions associated with metabolic and genetic illnesses have been reported (Table 3). In a study performed by Arunsundar et al, HT treatment (10 mg/kg/day) reversed the deficit of spatial and working memory induced by intracerebroventricular injection of Aβ1–42 oligomer (53). Similarly, in another mice transgenic model of AD, HT (5mg/kg/day) improved electroencephalography activity and cognitive behaviour (52). In these two studies, HT amelioration of AD-related cognition impairment appeared independent of APP processing, as HT feeding did not attenuate brain Aβ accumulation. A significant improvement in cognitive function was observed in AD genetic mice model supplemented with HT, with a 50 mg/kg dosage. In contrast to the previous studies, in these experimental conditions, behavioural and memory improvements were paralleled by a remarkable reduction of Aβ42 and pE3-Aβ deposits in the cortex and hippocampus (66). Other studies in the invertebrate organism Caenorhabditis elegans models of PD showed the ability of HT to reduce neurodegeneration, increasing locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure and preventing α-synuclein accumulation in dopaminergic and muscles cells (67,68).

Experiments based on in vitro and animal models have demonstrated that olive oil phenolic compounds such as HT and its metabolites are capable of protecting the brain from most of the molecular alterations that characterize the onset and progression of AD and PD. This effect is achieved primarily through the modulation of oxidative stress and neuroinflammation, as well as the reduction of deposition and toxicity of the altered proteins involved. As a result, studies using animal models have observed relevant improvements in cognitive performance. However, it is worth noting that concentrations used in these studies were high, and the bioactive compounds were administered acutely to achieve a measurable effect. These conditions are far from the physiological concentrations that are reached through the diet, which are lower and more extended in time. While in vitro and pre-clinical studies provide valuable information about the potential efficacy of olive oil phenolic compounds, caution should be exercised when extrapolating these findings to real-world scenarios.

Table 3. Effects of HT and derivatives in animal models.

Table 3. Effects of HT and derivatives in animal models.

Study	Animal model	Compounds tested	Dose	Route of administration	Significant outcomes	Ref.
Arunsundar et al., 2015	C57BL/6 mice treated with Aβ1–42 plus oA42i	HT	10 mg/kg/day for two weeks	Oral gavage	Reduction of brain pro-inflammatory factors (IL-18, IL-6, and COX-2) and modulation of MAPK signaling pathways. Restoration of Bcl-2/Bad levels and activation of caspase-dependent mitochondria-mediated apoptotic pathway involving cytochrome c, APAF-1, and caspase-9/3 induced by oA42i.	(53)
Zheng et al., 2015	Specific pathogen-free female Sprague–Dawley rats exposed to restraint stress	HT	10 - 50 mg/kg/day for two weeks before mating	Oral	Prevention of stress-induced downregulation of neural proteins BDNF, GAP43, synaptophysin, NMDAR1, NMDANR2A and NMDANR2B. Increase of low expression of glucocorticoid receptor. Increase of transcription factors FOXO1 and FOXO3, and phase II enzyme-related proteins Nrf2 and HO-1.	(58)
Peng et al., 2016	Transgenic APP/PS1 mice	HT	5 mg/kg/day for six months	Oral gavage	Modulation of mitochondrial oxidative dysfunction, measured as reduction of mitochondrial carbonyl proteins and GSSG, increased SOD expression, and restoration of phase II enzymes expression. Restoration of p38 and JNK/MAPK signaling and attenuation of inflammation in the cerebral cortex. Inhibition of brain apoptotic responses.	(52)
Nardiello et al., 2018	TgCRND8 and wild type mice	HT	50 mg/kg for four weeks	Oral gavage	Reduction of Aβ42 and pE3-Aβ deposits in the cortex and hippocampus. Marked reduction of TNF-α expression and astrocyte reaction and modulation of MAPKs signaling.	(66)
Calahorra et al., 2019	Male C57BL/6JRj mice which underwent transient occlusion of the right middle cerebral artery	HT	45 mg/Kg/day for five weeks	Oral (Incorporated into the pellets)	Improvement of recovery after ischemic stroke by ameliorating stroke-associated learning and motor impairments. Increase in cerebral blood flow, functional and structural connectivity, and anti-inflammatory and neurogenic activity.	(65)
Brunetti et al., 2020	Wild type C. elegans strain N2 (Var. Bristol) and transgenic C. elegans strain OW13	HT	30 μg/mL, 100 μg/mL, 250 μg/mL and 500 μg/mL,	Oral	Improvements of locomotive behavior and attenuation of autofluorescence as a marker for ageing. Enhancement of locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, reduction of α-synuclein accumulation in muscles cells, and prevention of neurodegeneration in α-synuclein-containing dopaminergic neurons.	(67)
D’Andrea et al., 2020	Btg1 knockout and Bgt1 wildtype strains (C57BL/6 background) mice	HT	100 mg/kg/day for 13 days	Oral (in drinking water)	Activation of neurogenesis in the dentate gyrus, increase of new neurons survival, and decrease of neuronal apoptosis.	(64)
Di Rosa et al., 2020	Wild type C. elegans strain N2 (Var. Bristol) and transgenic C. elegans strain OW13	HT	100–500 μg/mL.	Oral	Reduction of neurodegeneration, increase of locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure and prevention of α-synuclein accumulation.	(68)
Pérez-Barrón et al., 2020	Male Wistar rats PD model treated with MPP+	HT	Single dose 1.5 mg/Kg	Intravenous	Reduction of the number of ipsilateral rotations, correlated with the preservation of striatal dopamine levels, due to the inhibitory effect on MAO isoforms activity.	(61)
Zhang et al., 2020	Male C57BL/6 mice treated with LPS	HT	Single dose 100 mg/kg	Oral gavage	Reduction of some pro-inflammatory mediators (COX-2, iNOS, TNF-α, IL-1β) levels and microglia/astrocyte activation in the brain.	(56)
Fan et al., 2021	CUMS–induced depressive mice	HT	0.05 – 0.07 g/kg/day for four weeks	Oral gavage	Marked antidepressant effect by ameliorating HPA axis function, pro-inflammatory cytokine release, and tryptophan-kynurenine metabolism. Improvement of dysfunction of the hypothalamic-pituitary-gonadal axis and abnormal cyclic nucleotide metabolism.	(54)
Pathania et al., 2021	Male C57BL/6 mice treated with MPTP	HT	50 mg/kg/day for one week before and after MPTP administration	Oral gavage	Restoration of dopamine levels in the brain and prevention of loss of dopaminergic neurons in the substantia nigra and striatum through MAO-B inhibition.	(63)
Pérez-Barrón et al., 2021	Male Wistar rats PD model treated with MPP+	HT, HT acetate and nitro-HT	Single dose 1.5 mg/Kg	Intravenous	Protection from dopamine neuron degeneration, restoration of MPP+-induced redox unbalance, decrease of lipid peroxidation products and rise of GSH/GSSG ratio.	(62)
Qin et al., 2021	Transgenic APP/PS1 mice	HT acetate	50 mg/kg/day for twelve weeks	Oral gavage	Improvement of the escape latency, escape distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and decreasing inflammatory cytokine by modulating NF-ĸB activity and MAPK signaling.	(57)

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP+), amyloid β42 (Aβ42), apoptotic protease activating factor-1 (APAF-1), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), chronic unpredictable mild stress (CUMS), cyclooxygenase-2 (COX-2), Forkhead box protein O1 and O3 (FOXO1, FOXO3), glial fibrillary acidic protein (GFAP), glutathione reduced (GSH), glutathione oxidized (GSSG), Growth Associated Protein 43 (GAP43), heme-oxygenase-1 (HO-1), Hypothalamic-Pituitary-Adrenal (HPA), ibotenic acid (oA42i), inducible nitric oxide synthase (iNOS), interleuchin 1β, 6, 18 (IL-1β, IL-6, IL-18), Janus kinase/mitogen-activated protein kinase (JNK/MAPK), monoaminoxidase (MAO), N-methyl-D-aspartate receptor 1/2A/2B (NMDAR1, NMDANR2A, NMDANR2B), nuclear factor erythroid 2–related factor 2 (Nrf2), nuclear factor ĸB (NF-κB), pyroglutamate-modified Abeta (pE3-Aβ), superoxide dismutase (SOD), tropomyosin receptor kinase B (TrkB), tumor necrosis factor α (TNF-α).

4. Clinical evidence of the role of HT and derivates in cognitive decline

4.4. Clinical trials administering nutraceuticals with OO phenolic compounds

A nutraceutical formulation containing oleuropein, S-acetyl glutathione, piperine, bacopa, and vitamins B6, B12, E, and D3 was administered in an RCT (82) to patients with mild AD. The initial study design was a crossover RCT with two 6-month intervention periods. One with the administration of the nutraceutical formulation, and the second one without it. The study design suffered because of the COVID-19 pandemic, and participants only had time to undergo one of the two interventions. The number of participants included decreased to 18 from the 40 initially foreseen. Study participants underwent extensive cognitive evaluations at the beginning and end of the 6-month period. Despite the small sample size and relatively short treatment period, the active treatment triggered statistically significant changes in almost all cognitive outcome measures, including global cognition, memory, attention, and executive function. Caution is needed in interpreting results since the trial was not controlled with a placebo, and participants were not blinded to the treatment. These facts may be biasing observed results. Additionally, the described effects cannot be attributed solely to oleuropein but probably to a synergistic effect of the active compounds in the nutraceutical formulation. The authors agree that, given the particularities of the trial, this represents a proof-of-concept study. They claim to be planning a double-blind RCT with a larger sample size and including validated AD biomarkers.

Finally, and as an additional point, we have examined the ongoing research and identified two registered clinical trials specifically targeting EVOO phenols and age-related cognitive decline. The first study, identified as GOLDEN (NCT04440020), is an RCT that aims to evaluate the effect of a beverage made from OO leaves on cognitive performance in 100 patients with MCI (https://clinicaltrials.gov/ct2/show/NCT04440020). The second ongoing study is EVOCAD (NCT04229186), a pilot study investigating the effects of "coratina" EVOO in patients with MCI and AD. In this registered RCT, 24 participants will be administered either EVOO or refined OO. Researchers aim to evaluate its effect on cognitive performance, brain imaging, beta-amyloid, and other degradation biomarkers (https://clinicaltrials.gov/ct2/show/NCT04229186). Study has passed its completion date and status has not been verified in more than two years and publications reporting results are pending.

Nonetheless, we have identified several ongoing trials whose primary outcome is cognitive performance through administering a MedDiet intervention. Since EVOO is known as a major contributor to the health benefits of MedDiet, special attention should be paid in the future to the results obtained in these studies. Findings from all these ongoing studies will help to further enlarge the existing clinical evidence of the health effects of the phenols present in EVOO on cognitive maintenance.

Table 4. Characteristics of the reviewed studies on the effects of olive oil and its cognitive effects.

Table 4. Characteristics of the reviewed studies on the effects of olive oil and its cognitive effects.

Study	Type of study	Intervention	Control group	Health status at baseline	N and Duration	Measures of cognition	Significant outcomes of the interventions	Ref.
Valls-Pedret et al., 2012	Cross-sectional	Not applicable	Not applicable	High cardiovascular risk	477 NA	Cognitive performance (MMSE, RAVLT, WMS, WAIS and the Color Trail Test)	Total olive oil intake associated with immediate verbal memory	(70)
							Virgin olive oil intake associated with delayed verbal memory
							Total urinary polyphenols associated with better scores in immediate verbal memory
Martínez-Lapiscina et al., 2013 a	RCT	Int G1: MedDiet + EVOO (1L/week)	Low fat diet	High cardiovascular risk	285 6.5 years	Cognitive Performance (MMSE, CDT, WMS, RAVLT, ROCF, BNT, FAS, WAIS-IIIR and CDR) and Cognitive status (normal, MCI or dementia)	EVOO vs control: higher MMSE, ROCF immediate and delayed, FAS and digital forward scores	(72)
		Int G2: MedDiet + Nuts (30g/day)					EVOO vs nuts: higher ROCF immediate and delayed and verbal (VPA) memory domains
Martínez-Lapiscina et al., 2013b	RCT	Int G1: MedDiet + EVOO (1L/week)	Low fat diet	High cardiovascular risk	522 6.5 years	Cognitive Performance (MMSE and CDT) and incidence of dementia and MCI	EVOO vs Control: better MMSE and CDT	(71)
		Int G2: MedDiet + Nuts (30g/day)					EVOO: low odds ratio of MCI
Valls-Pedret et al., 2015	RCT	Int G1: MedDiet + EVOO (1L/week)	Low fat diet	High cardiovascular risk	477 4.1 years (mean)	Cognitive performance (MMSE, RAVLT, ASF, DST from WAIS, WMS and color trait test) summarized in 3 composites: memory, frontal (attention and executive function) and global cognition.	MedDiet+EVOO improved frontal cognition and global cognition adjusted composites for changes from baseline. Changes were significant compared to control group.	(73)
		Int G2: MedDiet + Nuts (30g/day)
Mazza et al 2018	RCT	MedDiet + EVOO (20-30g/day)	MedDiet	Healthy ≥ 65	180 1 year	Cognitive performance (MMSE and ADAS-cog)	ADAS-Cog score results improved following MedDiet and MedDiet+EVOO. The change following MedDiet+EVOO was higher vs control group.	(74)
Tsolaki M et al. 2020	RCT	Int G1: HP-EVOO (High phenolic: 975 mg/kg phenol) – 50mL/day	MedDiet	MCI (60-80 years)	50 1 year	Cognitive performance (MMSE, RBMT, ROCF, Trail making test parts A & B, ADAS-Cog, WMS DST, Fluency and CDT).	HP-EVOO improved ADAS-Cog and letter Fluency (follow-up vs baseline) compared to control group.	(75)
		Int G2: MP-EVOO (Moderate phenolic 271 mg/kg phenol) ) –50mL/day					MP-EVOO improved MMSE and ADAS-Cog (follow-up vs baseline) compared to control group.
Dimitriadis S et al, 2021	RCT	Int G1: HP-EVOO (High phenolic: 975 mg/kg phenol) – 50mL/day	MedDiet	MCI (60-80 years)	43 1 year	EEG resting-state with open eyes and close eyes conditions.	HP-EVOO decrease signal spectrum within 1–13 Hz and theta/beta	(76)
							HP and MP EVOOs improved the flexibility index across but was more noticeable in the HP- EVOO group.
		Int G2: MP-EVOO (Moderate phenolic 271 mg/kg phenol) ) – 50mL/day					HP-EVOO had a significant higher post-intervention reduction of nonlinearity index compared to the MP-EVOO and MedDiet groups.
Tzekaki E et al. 2021	RCT/ observational	EVOO	MedDiet	3 groups: MCI, AD and healthy	84 1 year	Fibrinolytic system (levels of PAI-1, a2-antiplasmin, tPA)	EVOO reduced PAI-1, and tPA in MCI, restoring levels to the ones of healthy individuals.	(77)
						AD hallmarks (levels of p-tau, Aβ1-42, Aβ1-40)	EVOO reduced p-tau in MCI restoring levels to the ones of healthy individuals. AB-40 levels were maintained with EVOO while they were downregulated in MCI without EVOO.
						Oxidative stress: levels of MDA	EVOO reduced MDA in MCI and restoring levels of healthy individuals
Tzekaki E et al. 2021	RCT/ observational	EVOO	MedDiet	Three groups: MCI, AD and healthy	80 1 year	Levels of BMI1, p53, tau, p-tau, Aβ1–42, Aβ1–40, TNF-a, IL-6 and MDA	EVOO intervention in MCI patients: increases BMI and decreases p53 and MDA concentrations were restored to healthy concentrations.	(78)
							IL6 and TNF-a concentration were downregulated in MCI patients by EVOO intervention.
							AD-related biomarkers (p-tau, Aβ1–42 and Aβ1–42/Aβ-40 ratio) restored to normal levels after administration of EVOO in MCI patients for 12 months.
Nishi et al., 2021	Observational	Not applicable	Not applicable	Overweight/obese + Metabolic syndrome	6647 2 year	Cognitive performance (MMSE, CDT, VFT-a and VFT-p, TMT A &B , DST-f & DST-b and WAIS-III ) an a a global compsotite	Baseline olive oil used as the primary oil was found to be positively associated with changes in global cognitive function and in working memory (forward and backward DSTs).	(4)
Kaddoumi et al., 2022	RCT	EVOO (1200 mg/kg of total polyphenols) (30mL/day)	Refined OO (null polyphenol content) (30mL/day)	MCI (55-75 years)	26 6 months	MRI: contrast-enhanced MRI and fMRI	EVOO decrease BBB permeability and brain connectivity.	(81)
						Cognitive performance (MMSE, CDR, WMS-IV)	EVOO and ROO decreased CDR and increased WMS-IV sub-sections.
						AD biomarkers Aβ40, Aβ42, Tau and p-tau181.	EVOO and ROO reduced Aβ42/Aβ40 ratio and p-tau/tau.
Marianetti et al. in 2022	RCT	Nutraceutical formulation with SAG (50 mg), oleuropein (80 mg), vitamin B6 (1 mg), B12 (3µg), vitamin E (15 IU), vitamin D3 (4 µg), piperine (3mg), bacopa dry extract (100 mg) twice a day.	Absence of nutraceutical formulation	Mild AD	1 6 months	Cognitive Performance (MMSE, CDT, RAVLT, RCF C, MA (attentive matrices), AAT, FAB, STEP, SVF, PVF.)	Cognitive deferioration: nutraceutical improved MMSE and CDT significantly vs control group.	(82)82
							Memory: nutraceutical improved RAVLT-immediate and delayed recall, and RCF-immediate recall vs a deterioration in control group.
							Attention: nutraceutical improved attentive matrices vs a reduction was observed in control group.
							Language & speech: nutraceutical improved AAT vs no change in control group.
							Executive functions: nutraceutical improved all measured indications vs a decrease in control group.

Alzheimer disease (AD); Animals semantic fluency (ASF); Attentive matrices (MA); Clinical dementia rating (CDR); Clock-drawing test (CDT); Digit Span test (DST) from Wechsler Adult Intelligence Scale (WAIS); Extra virgin olive oil (EVOO); Frontal Assessment Battery (FAB); High phenolic extra virgin olive oil (HP-EVOO); Mild Cognitive Impairment (MCI); Mini-mental state examination (MMSE); Moderate phenolic extra virgin olive oil (MP-EVOO); Progressive Matrices (Raven's) (PVF); Rey Auditory Verbal Learning Test (RAVLT); Rey-Osterrieth Complex Figure Copy (RCF C); Randomized Controlled Trial (RCT); Silhouettes subtest of the Visual Object and Space Perception battery (SVF); Stroop Test for Executive Processing (STEP); Wechsler Memory Scale (WMS); Wisconsin Card Sorting Test (AAT).

5. Conclusions

Table 5. Effects of EVOO phenolic compounds on the different cognitive domains.

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