Extra-Virgin Olive Oil Enhances the Blood-Brain Barrier Function in Mild Cognitive Impairment: A Randomized Controlled Trial

Abstract

Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-β (Aβ) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. 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 improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aβ₄₂/Aβ₄₀ and p-tau/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 EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.

Keywords: Alzheimer’s disease; amyloid beta peptides; blood–brain barrier; cognitive function; contrast-enhanced MRI; extra-virgin olive oil; functional MRI; mild cognitive impairment; refined olive oil; tau.

Figure 1

Trial profile.

Figure 2

Findings from MRI screen. Effect of 6-month consumption of ROO and EVOO on (A) Functional connectivity (FC) for overall connections shown in Table 2. The baseline is shown in red and the 6-month timepoint is shown in green, with (B) Visualization of connections shown in Table 2. Abbreviation: Middle Frontal Gyrus (MFG), parahippocampal gyrus (PHG), precuneus (PRCU), Postcentral gyrus (PoCG), lingual gyrus (LING), superior parietal lobule (SPL). L: left and R: right (n = 12 in each group); and (C) BBB permeability assessed as overall Gd extravasation in the hippocampus and PHG shown in Table 2. (D) Comparison of network variant locations between task and rest states. The left panel is for ROO group 6-month > baseline task-rest differences, and the right panel is for EVOO group baseline > 6-month task-rest differences. Please see Tables S1 and S2 for a listing of coordinates from the local maxima within the cluster for ROO and EVOO groups, respectively. Effect of 6-month consumption of ROO and EVOO on (E) CDR-SB, and (F) the number of participants who demonstrated improved learning memory (immediate and delayed) assessed by the WMS-IV logical memory test. Data are presented as mean + SD; ns is not significant, * p < 0.05, ** p < 0.01, *** p < 0.001 is a significant difference between baseline and 6 months post olive oil consumption.

Figure 3

Effect of ROO and EVOO on changes in blood levels of AD biomarkers in MCI participants after 6 months of daily consumption. (A) Aβ₄₀, (B) Aβ₄₂, (C) Aβ₄₂/Aβ₄₀ ratio, (D) t-Tau, (E) p-Tau 181, (F) p-Tau/t-Tau ratio, and (G) NfL. Data are presented as mean ± SD; ns is not significant, * p < 0.05, ** p < 0.01, *** p < 0.001 between baseline and 6 months post olive oil consumption.