Even though Alzheimer’s disease (AD) is the most common cause of dementia, the mechanisms governing the establishment and progression of the disease remain largely unknown. Here, we investigated the implication of the neuroprotective protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) in AD and the possibility to reverse the onset of the disease through the administration of extra virgin olive oil (EVOO) in Mild Cognitive Impairment (MCI) patients. For this purpose, we utilized a wide bank of MCI patient samples to examine the potential effects of EVOO. We found that while EVOO treatment increases BMI1 levels, p53 levels drop in MCI patient serum after EVOO treatment for 12 months. Additionally, AD-related biomarkers (p-tau, Aβ1-42 and Aβ1-42/Aβ-40 ratio) return to normal levels after administration of EVOO in MCI patients for 12 months. Moreover, we show that upon EVOO administration, BMI1-upregulation correlates with reduction of oxidative stress and inflammatory responses. In conclusion, we provide clinical trial evidence to confirm that restoration of BMI1 activity through EVOO administration in MCI patients constitutes a potential therapeutic approach against neurodegeneration leading to AD.Copyright © 2018. Published by Elsevier Inc.