There is precious little good news these days in the fight against Alzheimer’s disease – or so it seems.
As 2016 drew to a close, news came that a large clinical trial of a drug developed by Eli Lilly and Company, solanezumab, had failed to slow progression of the neurodegenerative disease – the most common cause of dementia.
That latest disappointing result for a potential drug puts patients back at square one: Although there are some drugs that have a modest effect on symptoms, there is not one medication that actually slows the degenerative process.
But lost amid that dispiriting headlines is an uplifting reality: Hardly a week goes without a significant new finding about Alzheimer’s disease. Each discovery is another chink in the disease’s armour, pointing to new targets, treatments and best practices.
The UBC Faculty of Medicine has become a major generator of those discoveries, and they are coming from all parts of the medical school: neurology, neuroscience, medical genetics, physical therapy and psychiatry.
The good news, however, comes out sporadically, diluting the potential cumulative impact. What follows is by no means a complete accounting of UBC’s contributions to the fight against Alzheimer’s disease. But it’s hard not to take hope from this partial overview – and from the near-certainty that the Faculty of Medicine will be logging more breakthroughs in 2017 and beyond.
An intriguing link between cancer and Alzheimer’s
Poul Sorenson has uncovered additional evidence linking Alzheimer’s disease to cancer. He discovered that an enzyme that helps tumour cells thrive under stress has the opposite effect – it actually hastens the death of neurons.
This “Jekyll and Hyde” dichotomy, published in October in Acta Neuropathologica, is welcome news, because it means that blocking that enzyme could be beneficial for either condition – in cancer, by weakening malignant cells’ ability to withstand stress, or in Alzheimer’s disease, by enabling brain cells to withstand assault from toxic protein fragments.
Dr. Sorenson, a Professor in the Department of Pathology and Laboratory Medicine and Senior Scientist at the BC Cancer Agency, found that the enzyme, eEF2K, allows cancer cells to survive in the face of nutrient scarcity – a common condition for cancer cells because they multiply so rapidly, often outstripping available sources of energy.
Dr. Sorenson and postdoctoral fellow Assad Jan figured the enzyme had the same protective effect on neurons, and that neurons simply can’t produce enough of it to counter the effects of amyloid-beta protein fragments – considered to be the main driver of Alzheimer’s disease.
To their surprise, they found mouse models of Alzheimer’s disease had elevated levels of eEF2K activity in their brains. They also found higher activity levels of the enzyme in brain tissue from deceased people who had Alzheimer’s.
When they created mice that were genetically engineered to be eEF2K-deficient, the neurons remained viable and continued to grow, even when exposed to amyloid beta in vitro. They also found that a worm model of Alzheimer’s disease, when engineered to be eEF2K-deficient, exhibited neurologically healthy behavior.
Dr. Sorenson believes that eEF2K controls the transmission of signals from one neuron to the next, but that amyloid beta somehow “hijack” it and send it into overdrive, creating oxidative stress – a series of biochemical reactions that damage a cell’s proteins, membranes and genes.
“We think there is a therapeutic window here,” Dr. Sorenson said. “The good news is, the clinical implication is the same, whether it’s cancer or Alzheimer’s disease – blocking eEF2K would be the goal, but for very different reasons.”
Underscoring the connections between Alzheimer’s disease and other conditions, Haakon Nygaard is exploring the potential of two drugs that were developed to treat epilepsy and cancer.
Dr. Nygaard, the Fipke Professor in Alzheimer’s Research in the Division of Neurology, found that brivaracetam, an anti-seizure drug still in clinical development for epilepsy, completely reversed memory loss in a rodent model of Alzheimer’s.
The findings, published in 2015 in Alzheimer’s Research & Therapy, reinforce the theory that brain hyperexcitability plays an important role in Alzheimer’s disease. The theory gained credibility as it became more widely known that patients with Alzheimer’s have an increased risk of seizures, especially in people with a family history of the disease.
Previous studies in both rodents and humans have shown that another epilepsy drug, levetiracetam, may slow some of the symptoms of Alzheimer’s disease, including memory loss.
“Larger clinical studies in human subjects will be needed before we can determine whether anticonvulsant drugs will be part of our future therapeutic arsenal against Alzheimer’s,” Dr. Nygaard said.
Although Dr. Nygaard’s study on brivaracetam relied on rodents, he is co-leading an $11 million clinical trial funded by the U.S. National Institutes of Health, that is testing another drug, saracatanib, that was developed for cancer.
Dr. Nygaard and his collaborators at Yale University (where he was previously a faculty member) zeroed in on saracatinib because of their interest in a protein called Fyn kinase, which they knew plays a central role in how amyloid beta wreaks havoc on neurons. Saracatanib targets Fyn kinase.
The team completed the first phase in Connecticut in early 2014, demonstrating the drug’s short-term safety. The next phase will aim to show, using PET, that the drug can arrest an Alzheimer’s-specific decline in metabolic activity in certain parts of the brain. The trial has enrolled 159 patients, including seven in Vancouver, and will conclude in December.
Probing the intricacies of exercise
Teresa Liu-Ambrose is a major contributor to the growing body of evidence about exercise’s potential to limit the damage done by Alzheimer’s disease.
One of her more recent studies showed the weightlifting may have had the most impact on preserving cognitive executive function and associated memory – the two traits most linked to dementia.
The study of 86 women compared weightlifting to walking and balance and tone exercises. Using functional MRIs, the women who lifted weights had the most robust brain function.
“We accept that exercise is the golden bullet,” Dr. Liu-Ambrose, an Associate Professor in the Department of Physical Therapy, told CNN. “But we need to identify who might benefit the most from what exercise.” That study, she said, was “one of the first times resistance training has been looked at in connection with Alzheimer’s.”
Another intriguing finding from that study: Those with a higher cognitive baseline gained the most benefits from exercise.
“You would think if you had more impairment, you would have more improvement, but this says the opposite,” said Dr. Liu-Ambrose, who is Director of the Aging, Mobility and Cognitive Neuroscience Lab. “This highlights that resistance training improves cognition, but you really have to consider a person’s cognitive abilities.”
An antibiotic’s intriguing effect
Another promising line of inquiry is being pursued by Brian MacVicar, who has found that an antibiotic can partially restore brain cell communication around areas damaged by amyloid plaques.
The antibiotic, ceftriaxone, is used treat bacterial infections, especially during surgery. Dr. MacVicar, a Canada Research Chair in Neuroscience and Co-Director of the Djavad Mowafaghian Centre for Brain Health, found that when cefitriaxone was applied to brain cells, it cleared away excess glutamate – a signaling molecule that accumulates in the areas around plaques. When glutamate fell to normal levels, neuronal activity was mostly restored.
Excess glutamate disrupts communication between neurons, leading to cell death, at a very early stage of Alzheimer’s disease, before memory impairment is detectable. So Dr. MacVicar’s findings, published in November in Nature Communications, open a window for an early intervention strategy to possibly prevent or delay neuronal loss.
Beyond work on cells, animal models and human clinical trials, the Faculty of Medicine’s researchers are finding ways to improve outcomes for people with Alzheimer’s.
A warning about poor advice, questionable motives
Julie Robillard, an Assistant Professor in the Division of Neurology, studies the proliferating sources of online advice about Alzheimer’s and other forms of dementia, and based on the patterns she sees, has been spreading the message, “Let the reader beware.”
She found many websites offered poor advice and about a fifth promoted products for sale. She has identified “red flags” for sources of low-quality information: recommendations of products for sale; very specific recommendations; use of strong language such as “cure” or “guarantee”; reliance on anecdotal evidence instead of empirical research.
Dr. Robillard and colleagues are developing a simple test of six questions that people can use to help recognize high-quality information.
“The few websites offering high quality information can be hard to distinguish from the many low-quality websites offering information that can be potentially harmful,” Dr. Robillard said.