This article is part of our October 2023 Cognition and Mental Health special issue. Download the full issue here.
Kaddoumi A, Denney TS Jr, Deshpande G, et al. Extra-virgin olive oil enhances the blood-brain barrier function in mild cognitive impairment: a randomized controlled trial. Nutrients. 2022;14(23):5102.
To prove or disprove that the phenolic fraction of extra virgin olive oil (EVOO) is responsible for the cognitive benefits of olive oil by comparing its effects with those of refined olive oil (ROO) in participants diagnosed with mild cognitive impairment (MCI)
Both refined olive oil and extra virgin olive oil show benefit against cognitive decline, but EVOO has broader effects.
This study examined the effect of daily consumption of ROO and EVOO for 6 months on blood-brain barrier (BBB) permeability (assessed by contrast-enhanced magnetic resonance imaging [MRI]) and brain function (assessed using functional MRI) in subjects with MCI as the primary outcomes in a randomized, controlled trial. Investigators also assessed cognitive function and Alzheimer disease (AD) blood biomarkers as the secondary outcomes.
Investigators recruited individuals with MCI from the community and assessed them for eligibility at Auburn University MRI Research Center, in Auburn, Alabama. Participants underwent neuropsychological evaluations for inclusion. Eligible participants were randomly assigned to either the EVOO or ROO group.
Twenty-six participants enrolled in the study. One did not complete the postintervention session and so was excluded from analysis. Thirteen participants were enrolled in the EVOO group and 12 participants in the ROO group. There were 5 men in the EVOO group and 3 in the ROO group. Those in the ROO group were slightly younger on average, 65.5 years vs 67.5. Otherwise, the 2 groups were comparable.
Both groups received 30 mL (2 tablespoons) of their olive oil per day. The EVOO group received an oil called The Governor from the Kyoord company. This EVOO contains 1,200 mg/kg of total polyphenols (see Kyoord.com). Those in the ROO group received Bertolli® Extra Light Olive Oil.
Study Parameters Assessed
Blood-brain barrier permeability (assessed by contrast-enhanced MRI) and brain function (assessed using functional MRI) were the primary outcomes assessed.
Cognitive function and AD blood biomarkers were also assessed as secondary outcomes. These markers included plasma concentrations of Aβ40, Aβ42, tau, and p-tau181, along with serum neurofilament light chain (NFL) levels. Investigators also used the Clinical Dementia Rating (CDR) to assess patients.
This proof-of-concept study was designed to evaluate EVOO in MCI participants and compare its effect with that of ROO (null in phenolic fraction).
EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it also improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. EVOO and ROO significantly reduced blood Aβ42/Aβ40 and phosphorylated (p)-tau/total (t)-tau ratios, suggesting that both altered the processing and clearance of Aβ. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting it was the EVOO phenols that contributed to this effect.
The authors declare no conflict of interest. However, the lead and corresponding author, Amal Kaddoumi, is a cofounder and equity shareholder in Oleolive, LLC. This company produces and markets polyphenol concentrates from olive oils; specifically they hope to commercialize a specific phenol called oleocanthal. This company did not supply either of the olive oils used in the current study.
Practice Implications & Limitations
At this point in time, we are well aware that olive oil is good for you. Higher intakes of olive oil are associated with significant improvements in total mortality and disease-specific deaths from cardiovascular, cancer, neurodegenerative, and respiratory diseases.1 Recent studies suggest that EVOO also has a significant effect on memory and alters blood markers for Alzheimer disease for the better. In her study published in 2020, Magda Tsolaki reported that in volunteers given 50 mL EVOO/day for a year, both high and moderate levels of phenols were associated with improved scores for those with mild cognitive impairment and also with a significant reduction in the AD marker APOEɛ4.2 In December 2021, Elena E Tzekaki provided further follow-up on this group of study participants. Those who had received EVOO had experienced drops in their AD markers so that their levels were no longer distinguishable from the healthy study controls who did not display symptoms of cognitive impairment.3
The authors of this current study, Kaddoumi et al, have in recent years reported that EVOO has a beneficial effect on Alzheimer disease in mice, reducing various biomarkers of the disease and improving memory function.4,5 These results led to their current trial in humans. The trial is interesting as the authors compare the effect of a high-phenolic-content olive oil (EVOO) with a refined olive oil (ROO) in which the phenolic content was negligible. This current study lasted only 6 months.
The EVOO appeared to have significant advantages over the ROO. It was associated with enhanced functional connectivity and reduced BBB permeability. Past research suggests that the blood-brain barrier begins to breakdown before the brain atrophy or dementia of Alzheimer disease are apparent. Alterations in blood-vessel morphology appear to even precede changes in BBB permeability. The EVOO appears to have protected against these changes, whereas the refined oil did not. While the EVOO may be superior in these aspects, both oils were associated with some benefit. Both oils were associated with significant improvements in memory based on the CDR rating.
There is a significant difference in cost between the 2 oils used in this study that must be acknowledged. The EVOO used, a product called The Governor from Kyoord Company, is currently sold online for $80/500 mL bottle. The refined olive oil, Bertolli® Extra Light, sells online for $60/ 2,000 mL. In this study, participants consumed 50 mL/day. The EVOO would cost $8/day to take, while the ROO would cost just $1.50 per day. While the EVOO may have greater benefit, it may be challenging, based on current evidence, to convince patients to invest this much money in olive oil.
My immediate reaction is to wonder if there might be other sources of olive polyphenols that would provide high levels of polyphenols at a lower cost than the high-priced EVOO used in this study? Olive trees increase production of polyphenol chemicals to defend themselves against insect attack, fungal, bacterial, or viral infections, excessive sun exposure, and lack of water. Such stressors are common in the Mediterranean environment where olive trees originated and are grown. It might be possible to manipulate the trees’ growing environment to increase the polyphenol content of their oils. Actually, some companies already advertise that they purposefully stress their olive trees to increase polyphenol content.
There is a significant difference in cost between the 2 oils used in this study that must be acknowledged.
Olive trees also produce and accumulate stores of polyphenols in other parts of their structures. Efforts are well-underway to use both the leaves and olive pits as a source of polyphenols for nutraceutical extracts. It makes ecological sense to repurpose the olive leaves, which are traditionally trimmed from olive trees but not used afterwards, and which typically end up as waste material.6
Up to this point, I’ve made the common assumption that the dose/response curve between polyphenol exposure and prevention of cognitive decline is a straight line—that is, the higher the dose of polyphenols administered, the greater their effect at protecting the brain. Consider, though, that the action of many biologically derived substances we employ in our practices are not straight lines but rather U-shaped curves with a sweet spot at which a specific dose produces an optimum response that lessens at lower or higher concentrations. Such U-shaped dose responses are sometimes referred to as hormetic responses. Nothing in the data reported in these recent studies argues that more is better, only that some polyphenols are more helpful than almost none. This study by Kaddoumi et al compared olive oils at either extreme, from highest polyphenol content to lowest. Nothing in their data excludes the possibility that some intermediate concentration of polyphenols might be even more effective. At this point, all we can say is that daily doses of olive oil are helpful, and so far, the higher polyphenol content in EVOO has superior effect. Until there are results from clinical trials using a range of oils with varying polyphenol contents, we can only guess what to tell patients as to how much money they need to spend on their oil to achieve the best cost/benefit balance.