Apoaequorin, a calcium-binding protein originally isolated from the Aequorea victoria species of jellyfish, can improve several domains of cognitive function in older adults experiencing mild but troublesome impairment.
The soon-to-be published Madison Memory Study, involving 218 adults, aged 40-91 years, with self-reported memory concerns, shows that daily consumption of a dietary supplement containing 10 mg of apoaequorin, can improve scores on several objective measures of recall, executive function, and cognition.
Researchers assessed each patient using the CogState suite of standardized, computer-based cognitive function tests. The system includes: the Groton Maze Learning task, the Groton Maze Delayed Recall task, and the One Card Learning task, and the International Shopping List test, among others. Testing sessions took between 35 and 60 minutes, depending on the patient’s speed.
The investigators also used the AD8 Dementia Screening interview, to determine the extent of any cognitive dysfunction in each case. The patients were then randomized in a 2:3 ratio to 90 days of treatment with either placebo capsules (containing white rice flour) or identical capsules containing rice flour plus 10 mg Apoaequorin. They were re-tested with the CogState task series on days 8, 30 and 90 following initiation of treatment.
All patients had expressed concerns about memory loss. The investigators excluded those with history of uncontrolled hypertension, untreated psychosis or major depression, or significant neurological diseases. There were 148 women and 70 men completing the study; they had a mean age of 62.5 years. The placebo arm consisted of 92 subjects, and the Apoaequorin arm had 126.
The Madison Memory Study was conducted by researchers at Quincy Bioscience, a nutraceutical company that has developed an Apoaequorin supplement product.
Improving Calcium Homeostasis
Though derived from a marine coelenterate, Apoaequorin is very similar in its amino acid sequence to a human endogenous calcium-binding protein.
Neuronal cells need to maintain low levels of cytosolic calcium in order to function properly. As people age, there is a decline in endogenous calcium binding proteins, leading to a gradual increase in cytosolic calcium, and a progressive dysfunction of the neurons.
Age-related intracellular calcium dysregulation is associated with indicators of cognitive dysfunction and dementia, including amyloid precursor protein mutations, Apo-e4 expression, amyloid plaque formation, tau protein hyperphosphorylation, and synaptic dysfunction.
Preclinical studies of Apoaequorin show that it can regulate intracellular calcium levels, and protect neurons from ischemic cell death. In this sense, it represents a novel approach for preventing age-related cognitive decline.
Patients taking Apoaequorin showed a significant improvement in performance on the Groton Maze Learning task between baseline and Day 90. This test assesses a person’s ability to find a pathway through a 100 x 100 grid of “tiles” based on trial & error tile selection. The number of errors made in solving the maze puzzle decreased by 18.8% among the Apoaequorin patients. The placebo-treated patients showed a 10.6% decrease in errors.
The effect was even larger on the Groton Maze Recall task, which asks the subject to reproduce the maze-solving pathway they discovered earlier during the “learning” portion of the test. People taking Apoaequorin showed a 29% reduction in number of errors from baseline to Day 90; those on placebo showed a 4.4% reduction.
This suggests Apoaequorin has a strong positive effect on short term memory function.
The One-Card Learning test flashes images of playing cards. Each time a card is shown, the system asks if this card has been shown before. Sixty-one percent of the Apoaequorin patients showed improved performance from baseline to Day 90. Similarly, they showed improvement in performance on the International Shopping List Recall task, which asks subjects to remember items from a shopping list they were shown earlier in the testing session.
Though the changes from baseline to Day 90 were significant for both these tasks, the differences between the Apoaequorin and placebo groups were not. Placebo-treated patients also showed improvements on these two tasks.
The investigators noted some cognitive improvements among subjects who showed moderate-to-severe cognitive impairment at baseline, but these changes were not statistically significant. Apoaequorin clearly had more impact on people with mild to moderate impairment, suggesting a role for this compound in preventing progression from mild dysfunction to frank dementia.
Many Potential Benefits
Mark Underwood, Quincy Bioscience’s co-founder and president, presented the Madison Memory Study data earlier this summer at the Alzheimer’s Association International Conference in Paris. “Our next step is a larger scale study specifically targeting the Alzheimer’s population.” Quincy produces Apoaequorin as a dietary supplement called Prevagen.
The molecule was initially discovered 45 years ago by researchers studying the simple but elegant nervous systems of jellyfish. It is a critical component in jellyfish bioluminescence, and has been used for many years as a trace marker for various cellular biochemical processes. In 2008, Osamu Shimomura, Martin Chalfie, and Roger Y. Tsien, won the Nobel Prize for Chemistry for their work on practical applications of Apoaequorin in biochemistry.
The discovery of Apoaequorin’s calcium-binding capacity led the Quincy team to the idea that the compound might have a role in preventing cognitive dysfunction and maintaining memory. “The Alzheimer’s research community has known for some time that unregulated calcium is a culprit,” explained Mr. Underwood. Prior to the development of Apoaequorin, there were no treatments that addressed this pathogenic mechanism.
Taking Apoaequorin will not cause unnatural glowing in the dark, nor will it improve one’s ability to swim long distances underwater or sting one’s enemies. In fact, the product is no longer extracted from jellyfish at all. Quincy Biosciences developed systems to produce massive amounts of Apoaequorin from cell culture sources, obviating the need to hunt and destroy marine animals, and eliminating the risk that ocean pollutants could end up in the finished products.
Since it is similar to endogenous human calcium-binding proteins, apoaequorin is virtually free from side effects and drug interactions. It has shown no toxicity in any studies so far. Though it does bind calcium, this occurs primarily in the nervous system; it does not cause any problems when used in conjunction with calcium channel blockers or other calcium-modulating pharmaceuticals. There is no known cardiac or muscular effect from apoaequorin.
Since maintenance of calcium homeostasis is essential for proper neuronal function, Mr. Underwood believes Apoaequorin may have a role in the care and support of people with a host of neurological problems. To explore these possibilities, Quincy launched a series of studies called the HOPE Trials, exploring the potential of Apoaequorin in multiple sclerosis, migraine headaches and peripheral neuropathy.