Brazilian Green Propolis Improves Cognitive Function in Elderly People Living at High Altitude

Microglial-mediated neuroinflammation, systemic inflammation, and oxidative stress are key contributors to the cognitive decline in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Living at a high altitude exposes people to a hypoxic environment, resulting in increased oxidative stress and greater risk of cognitive decline. Propolis is produced by honey bees mixing plant resins collected from the local flora with beeswax, pollen, and their digestive enzymes. Propolis has antioxidant, anti-inflammatory, and neuroprotective properties. These authors previously showed that Brazilian green propolis (BGP) reduced systemic inflammation and microglial-mediated neuroinflammation. BGP significantly inhibited the hypoxia-induced release of proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6, by microglia. The purpose of this randomized, placebo-controlled, double-blind study was to assess whether BGP protects against systemic inflammation and cognitive decline in elderly people living at high altitude.

Subjects (n = 60; mean age, 72.8 years) living on the Qinghai-Tibet Plateau in Qinghai, China (altitude, 2260 meters), participated in this study conducted at the Institution of Geriatrics of Qinghai Provincial Hospital in Xining, Qinghai, China, from December 2013 to November 2015. Excluded subjects had a chronic or acute infection, neoplasia, treatment with nonsteroidal anti-inflammatory drugs or corticosteroids, C-reactive protein levels >10 mg/L, vascular dementia, or other physical or chemical factors causing dementia such as intracranial lesions.

Subjects received 6 capsules daily of either placebo (not described) or BGP ethanol extract (0.83 g/day) for 24 months. The BGP and placebo were provided by Yamada Bee Company, Inc.; Okayama, Japan. BGP contains mainly prenylated derivatives of cinnamic acid, with artepillin C being the major component. Each capsule of BGP contained a minimum of 11.0 mg artepillin C. Blood and urine samples were collected, and the Mini-Mental State Examination (MMSE) was conducted at baseline and 6, 12, and 24 months. The primary outcome measure was cognitive function as measured by the MMSE. As the cognitive function is closely related to systemic inflammatory level, the secondary outcome measures were systemic cytokine levels, including IL-1β, IL-6, TNF-α, IL-10, and transforming growth factor β1 (TGFβ1). Laboratory tests to assess safety included serum chemistry, hematology, and urinalysis. Compliance and adverse event monitoring protocols were not reported. At baseline, sociodemographic characteristics, MMSE scores, and cytokine levels did not significantly differ between groups.

Mean MMSE score for the BGP group gradually improved over time, while the mean score for the placebo group declined. Statistical analysis indicated a treatment response emerged over time (time points × group interaction, P = 0.016) and a significant treatment group effect (placebo × BGP, P = 0.007).

Serum levels of the proinflammatory cytokines IL-1β and IL-6 increased in the placebo group and decreased in the BGP group over time; both the time points × group interaction and treatment group effect were significant (P < 0.0001 for both). Analysis of TNF-α levels showed a treatment response emerged over time (time points × group interaction, P < 0.0001) and the treatment group effect approached significance (P = 0.0528). Serum levels of the anti-inflammatory cytokine TGFβ1 decreased in the placebo group and increased in the BGP group, with a significant response over time (time points × group interaction, P < 0.0001) and significant treatment group effect (P < 0.0001). Serum IL-10 was significantly different between groups (P = 0.0411).

At 12 and 24 months, IL-1β levels were negatively associated with MMSE scores, and TGFβ1 levels were positively associated with MMSE scores. All laboratory parameters remained within normal limits throughout the study. There were no significant differences between groups over time in alanine aminotransferase, aspartate transaminase, gamma-glutamyltransferase, blood glucose, total cholesterol, low-density lipoprotein cholesterol, uric acid, β-2-macroglobulin, and creatinine. The authors state that the results of the laboratory tests support the safety of BGP supplementation for 24 months.

The authors conclude that the significant decline in mean MMSE score indicates that MCI developed in subjects in the placebo group over the 24-month study and the cognitive decline was associated with an increase in inflammation markers from 6 months onward. In contrast, BGP was associated with an increase in MMSE score from 12 months onward and a decrease in inflammation marker concentrations from 6 months onward. The authors conclude that BGP may be an effective treatment for cognitive decline and reducing the risk of AD; however, further studies are needed to confirm this hypothesis. This study has many strengths and limitations. A strength is that the subjects were followed for 24 months. A limitation is the small population size. Of note is that the study population was living at high altitude so the findings may not be transferable to other populations.

The study was funded by Grants-in-Aid for Scientific Research (Japan Society for the Promotion of Science; Tokyo, Japan) and Yamada Research Grant (Yamada Bee Company, Inc.). The authors declare no conflict of interest.


Zhu A, Wu Z, Zhong X, et al. Brazilian green propolis prevents cognitive decline into mild cognitive impairment in elderly people living at high altitude. J Alzheimers Dis. 2018;63(2):551-560. doi: 10.3233/JAD-170630.