Olive oil's secret weapon against Alzheimer's: phenolic compounds

By Dr. Sanchari Sinha Dutta, Ph.D.Feb 12 2024

A review article published in the International Journal of Molecular Sciences provides a comprehensive overview of the efficacy of extra-virgin olive oil and its phenolic compounds in preventing and treating Alzheimer’s disease.

Review: Extra-Virgin Olive Oil in Alzheimer’s Disease: A Comprehensive Review of Cellular, Animal, and Clinical Studies. Image Credit: luigi giordano / Shutterstock

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory impairment, and difficulty performing daily activities. About 60-80% of all dementia cases are associated with AD. In the United States, AD is the sixth leading cause of death among older adults aged 65 years and above.

Two major neuropathological hallmarks of AD include the accumulation of amyloid-beta plaques and the formation of neurofibrillary tangles in the brain. Another pathological feature of AD is increased permeability of the blood-brain barrier, which facilitates the entry of harmful substances and immune cells into the brain, leading to the induction of neuroinflammation and oxidative stress.

The current AD treatments include therapeutic monoclonal antibodies, acetylcholinesterase inhibitors, and N-methyl-D-aspartate (NMDA) antagonists. Although these medicines effectively reduce symptom worsening and improve overall quality of life, they fail to cure the disease or prevent its progression.

A large pool of evidence highlights the positive impact of the Mediterranean diet in treating and preventing AD. Extra-virgin olive oil is the principal constituent of the Mediterranean diet, and it contains more than a hundred phenolic compounds, including oleuropein aglycone, oleuropein, oleocanthal, oleacein, tyrosol, and hydroxytyrosol. These compounds are known to reduce the risk of developing mild cognitive impairment and AD. 

Impact of extra-virgin olive oil and its phenolic compounds on AD hallmarks

Extra-virgin olive oil and its phenolic compounds prevent pathological hallmarks of AD through various pathways. They disrupt the aggregation of amyloid-beta peptides, increase their clearance from the brain, and prevent neuronal damage and oxidative stress.

These compounds inhibit the hyperphosphorylation of tau proteins, leading to the cessation of neurofibrillary tangle formation and the preservation of vital neuronal transport systems. Furthermore, they maintain the integrity of the blood-brain barrier and restrict the transportation of neurotoxic substances in the brain.

Robust anti-inflammatory and antioxidant properties of phenolic compounds play vital roles in preventing neuroinflammation and oxidative stress in the brain, which in turn is necessary for restricting further worsening of AD-related pathologies.

Preclinical studies investigating extra-virgin olive oil and its phenolic compounds

Several in vitro studies have investigated the antioxidant and neuroprotective properties of extra-virgin olive oil extracts and their therapeutic benefits against AD. In neuroblastoma cells, pretreatment with extra-virgin olive oil extracts has been found to induce the expression of key antioxidant enzymes and subsequently prevent free radical-induced oxidative damage. 

Individual phenolic compounds of extra-virgin olive oil, such as hydroxytyrosol and oleuropein, have been found to prevent translocation of nuclear factor kappa B (NFkB) in the nucleus, leading to reduced production of pro-inflammatory mediators and prevention of neuroinflammation mediated by microglia. Besides inhibiting pro-inflammatory cytokine production, these compounds increase the production of anti-inflammatory cytokines.

Combination treatment with oleuropein aglycone and hydroxytyrosol in neuroblastoma cells has been found to activate autophagic flux, reduce free radical production, prevent mitochondrial dysregulation, and inhibit cell damage caused by amyloid-beta plaques.

Several studies have highlighted the efficacy of oleocanthal in reducing AD pathological hallmarks. The compound has been found to increase the clearance of amyloid-beta plaques from the brain across the blood-brain barrier and stimulate their degradation.

Several in vivo studies with AD mouse models have demonstrated the therapeutic benefits of extra-virgin olive oil and its phenolic compounds. The treatment of mice with an extra-virgin olive oil-enriched diet has improved behavioral performance and synaptic integrity, reduced amyloid-beta accumulation and tau protein phosphorylation, and increased autophagy and amyloid-beta clearance.

Oleuropein-rich olive oil has been found to improve amyloid-beta-related pathologies, prevent neuroinflammation, enhance non-amyloidogenic pathways and synaptic markers, and improve memory performance in mice.

Treatment of mice with oleocanthal has been found to restore the blood-brain barrier integrity, increase autophagy, prevent neuroinflammation, suppress the RAGE/HMGB1 pathway, restore brain ATP level, mitigate anxiety and sleep disturbance, improve spatial working memory, and extend lifespan.

Clinical studies investigating extra-virgin olive oil and its phenolic compounds

Many human clinical trials have assessed the therapeutic efficacy of extra-virgin olive oil. An Italian study conducted on individuals aged 65 years and above has shown the protective efficacy of dietary monounsaturated fatty acid intake against cognitive decline. A systematic review assessing the relationship between the Mediterranean diet and cognitive impairment has found that higher adherence to the diet is associated with a significantly reduced risk of developing AD.

A study conducted on mild cognitive impairment patients has shown that intake of extra-virgin olive oil for over 12 months is associated with increased levels of neuroprotective proteins in serum, which in turn is associated with a reduction in oxidative stress and inflammation. The extra-virgin olive oil treatment has also been found to modulate AD-related biomarkers in the blood.

Another study on mild cognitive impairment patients revealed that Greek high-phenolic early-harvest extra-virgin olive oil and moderate-phenolic extra-virgin olive oil have higher efficacy in improving cognitive performance than the Mediterranean diet.

A recent pilot study has shown that intake of extra-virgin olive oil for six months is associated with increased brain functional connectivity, improved blood-brain barrier integrity, and improved memory in mild cognitive impairment patients. A significant enhancement in cognitive function has also been noticed in older adults consuming extra-virgin olive oil- or nut-supplemented Mediterranean diet.

In mild AD patients, a combination of oleuropein and S-acetyl glutathione has been found to significantly improve cognitive functions, memory, executive functions, and behavioral disorders.  

Overall, the results of preclinical and clinical studies highlight the protective efficacy of extra-virgin olive oil and its phenolic compounds against AD development and progression.