Modern medical advances are helping us live longer than ever before, but long life comes with its own challenges and perils. Some are inconvenient, some dangerous, but none are as feared for their impact on a patient’s mind and identity as Alzheimer’s disease. Little understood, Alzheimer’s, which is projected by the Alzheimer’s Association 2015 to affect 14 million people worldwide by 2050, strikes seemingly at random, robbing its victims of their memories, independence and ultimately, their lives. For over 30 years, Alzheimer’s research was focused mainly on amyloid plaques – protein deposits left behind in the brain of the afflicted. At the world-renowned Gladstone Institute of Neurological Disease in California, however, a promising young researcher named Yaisa Andrews-Zwilling, following in her mentor’s footsteps, is taking another path to a cure for the disease as she searches for answers in our genes. Her research focuses on apolipoprotein E4, a variant of apolipoprotein E (commonly known as ApoE), a protein integral to the functioning of the brain and nervous system. Researchers at Gladstone Institute have identified this APoE4 variant, which occurs in 25 per cent of the US population, as a significant genetic risk factor for the onset and progress of Alzheimer’s. Dr. Andrews-Zwilling is currently working at SanBio Inc., a company which develops regenerative therapies, using adult stem cells, for neurological disorders, including stroke, traumatic brain injury, spinal cord injury and retinal degeneration. SanBio Inc is a scientific leader in cell therapies for regenerative medicine and clinical testing for SanBio’s products is underway.

NIHERST interviews Yaisa Andrews-Zwilling

Q: How did you become interested in science and in your current field?
A: I was very good at the sciences with an excellent and very supportive biology teacher and amazing parents who encouraged me every step of the way. I first wanted to be a medical doctor doing biochemistry at The University of the West Indies, but later learned that although medical doctors are extremely important, their work depends upon researchers, who do a lot of the groundwork in creating drugs and helping us understand the body. That intrigued me.

Q: You did your masters and doctorate in neuroscience at the Max Planck Institute in Germany, one of the most prestigious scientific and technological academic institutions in the world. What was that experience like?
A: During my masters, I was actually really homesick. Of course I appreciated how lucky I was to have been among the 11 who were chosen out of 400 applicants interviewed that year, but I wasn’t sure I could stick it out. My parents, in their wisdom, wouldn’t let me come back to visit that first year. The intensity of the programme itself was not as bad as the homesickness. But my peer group was made up of other young scientists who were also a
long way from home. I had friends from Poland, Siberia, Australia and Ireland so we relied on each other. Those close friendships helped me through. And then I met my husband who was also a student there, which really helped! I stayed on at Max Planck to pursue my PhD. During my time in Goettingen, I was able to learn from Nobel Prize winners and scientists who are the very best of the best in their respective fields. It was an amazing
opportunity!

Q: What motivated you to study this disease?
A: My initial interest in neuroscience came because I was fascinated by how this organ in our head controls our actions and thoughts from infancy – body, mind and soul. My parents would fly me home every year to visit my wonderful extended family, including my grandfather who really made me feel like his preferred grandchild. While I was in Germany, he had a stroke. It was shocking to see his deterioration from this 6’ 4” strapping, amazing father figure to almost a child again. He started thinking I was my mother, and later not recognising me at all. And that changed the direction I wanted to go with the research. At first, I was fascinated with the brain in general but after what happened to my grandfather, I got interested in why some people age through 80, 90, 100 even – and have relatively good cognitive abilities, and why others don’t and by their sixties already have Alzheimer’s; why someone would suffer a stroke and recover completely and why someone else, like my grandfather, would have a stroke and completely deteriorate afterwards. I wanted to know how that happens and how I could prevent that from happening.

Q: You and your mentor Yadong Huang received a patent for your work on the APOE gene. Can you tell us more about the research that led you to your discoveries?
A: I started off working on the basic communication between brain cells during my PhD, trying to figure out exactly how two nerve cells talk to each other. Later, of course, I decided I wanted to work on the sequence of events that leads to neuro-degeneration and how we could prevent it. Eventually, I came to the Gladstone Institutes in the United States where I started working on Alzheimer’s disease. I started looking at a protein called
Apolipoprotein, which is a mouthful, so we just refer to it as ApoE4. This is a genetic risk factor that increases your likelihood of getting Alzheimer’s disease. The risk of getting Alzheimer’s disease doubles if you have one ApoE4 gene and increases 10-fold, if you have two copies. ApoE is a protein we all have. Most of us have the so-called “normal” form of the protein, ApoE3, which helps maintain the cholesterol level in your blood, and has a role in transferring fats and cholesterol to repair injured brain cells. The other isoform – or type – of the protein is ApoE4, which can’t do its job properly and predisposes you to getting Alzheimer’s. One in four persons has this protein. I really think Alzheimer’s is one of the worst diseases. It really robs you of you. You lose yourself before you pass away.

Proteins are made of up amino acids, like pearls on a string, arranged in a 3-D structure. ApoE3 sort of resembles a V-shape. ApoE4 is similar but looks like a tight U. Because of this abnormal shape, your cells see it as toxic, and try to get rid of it, keeping it from doing its job of transporting lipids to rebuild your brain cells. Not only is it stopped from doing its job, when they cut up this protein to get rid of it, the pieces are also toxic. So that is
what our team at Gladstone are working on, coming up with a drug to fix that problem. They are called “structure correctors” and they fit inside the tight U and open it back up, making the abnormal E4 form look more like the E3 form and allowing it to do its job. We are making it useable in animal models, and then will take it to clinical trials to test on humans.

Now, one of the major milestones we’ve had is figuring out the role of specific neurons called interneurons, which act as the brain’s brakes. Interneurons help the brain to focus on what it needs to and to ignore information it doesn’t need, managing interactions between nerve cells. My work published in 2010 and 2012 showed that interneurons are the first set of cells that we and other animals lose when Alzheimer’s progresses. These cells help to refine memories and retrieve memories but are lost by individuals with ApoE4 during the progression of Alzheimer’s. We were the first to show interneurons’ involvement in the memory retrieval process and that they are the first to be lost in Alzheimer’s. So that’s what my patent is based on – the role of these interneurons with respect to ApoE4 as well as another protein called tau, and how that cell loss in Alzheimer’s disease is related to learning and memory.

Q: You weren’t the first Gladstone researcher to work on APOE. Why the initial focus on APOE4 in Alzheimer’s disease?
A: After founding the Gladstone Institutes, Dr Robert Mahley initially worked on ApoE4’s effect on cardiovascular disease. Dr Alan Roses found the link between ApoE4 and Alzheimer’s, and Dr Yadong Huang and many others continued this work. Interest in ApoE4 is spreading now but they were a couple of the pioneers.

Q: What is the connection between brain plaque and Alzheimer’s?
A: The protein responsible for plaque is called amyloid which is what people normally think about when they think of Alzheimer’s disease. Amyloids are naturally occurring in everyone. Their role isn’t fully understood but if you have a mutation in this protein, or a change caused by aging, it gets deposited into the brain and causes amyloid plaques which are what most people associate with AD. Most research over the last 30 years has focused on amyloid. But pharmaceutical companies have yet to find a cure, so some focus is now moving to ApoE4 and other key proteins like tau. It’s the best time to be researching in this field.

Q: Some of your research has been on traumatic brain injury in relation to ApoE4. How are they connected?
A: With traumatic brain injury (TBI), there’s physical trauma. A car accident or an explosion for soldiers or sports injuries- those things cause cell death or nerve death in the brain. If you have ApoE4, again your chances of having a detrimental effect after TBI is much more likely, and that’s another thing that got me into this area of research.

Q: Do the drugs you are working on at Gladstone just prevent the risk or pre-disposition for Alzheimer’s or will they also slow or even reverse the progression of Alzheimer’s in someone already diagnosed with it?
A: By the time family members start noticing that something is wrong and you get diagnosed, in most cases your brain has already deteriorated. A lot of the discussion is related to how we can prevent it from happening. The ApoE4 drug not only helps in repairing brain cells, but in neurogenesis, which is the making of new brain cells. So new brain cells may be able to integrate and store new memories which will hopefully help, but it’s difficult or next to impossible to get back memories that were lost.

Q: Is there anything more that can be done to prevent Alzheimer’s?
A: The major rule of thumb is “what is good for your heart is good for your head”. So avoid high blood pressure, obesity, diabetes, cardiovascular disease- basically a healthy lifestyle with a diet that is not too high in fat and which includes exercise. There have been clear epidemiological links shown between those factors and Alzheimer’s disease.

Q: What treatments are there that help prevent Alzheimer’s? What drugs are there currently for Alzheimer’s and how do they work or relieve its symptoms?
A: There are four different FDA-approved drugs including one that does improve cognitive function at a very early stage, but there is no cure as yet.

Q: Which emerging technologies, recent discoveries or new understanding do you think will have a significant impact on Alzheimer’s research and neuroscience in general in the future?
A: Stem cell technology. It has revolutionised science and Shinya Yamanaka, who won the Nobel Prize for it, also works here at Gladstone. We no longer need stem cells from embryos. Thanks to his work, we can take body cells like skin and turn certain genes off or on to change those skin cells back into stem cells, then make any human body cell you want to make. The ability to restore stem cell-like properties to somatic (skin) has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies.

Q: Gladstone does outreach to high school students. What sort of outreach do you do?
A: The Institute’s main mission is to find cures for particular diseases afflicting mankind: virology, immunology, cardiovascular, neurology, but it also does outreach and communication in the neighbourhood, within the country and in general. Incidentally, as an intern in Trinidad, I worked at NIHERST’s Science Centre which is how I discovered my interest in science education. I learned how to explain relatively complex themes to lay
audiences, a skill that scientists don’t always have. At Gladstone I put that skill to use. We do a lot of outreach at high schools and universities. We explain career paths in science and what you have to do to be a scientist. And students also get to see that someone who looks like me can be a scientist!