Alzheimer’s Research–The Road Ahead: A Q&A with the NIA Director of Neuroscience

Statistics illustrate the extent to which Alzheimer’s disease is prevalent in the United States. It is the sixth leading cause of death in the United States and nearly 5.2 million Americans of all ages have this disease in 2013. In fact, it is estimated that in 2013, Alzheimer’s will cost the nation nearly $203 billion and the cost is expected to rise to $1.2 trillion by the end of 2050.2 These numbers all raise concerns as to what is essentially going on about Alzheimer’s research, diagnosis, treatments and prevention.

November is Alzheimer’s Awareness Month. The Princeton Public Health Review reached out to Dr. Neil Buckholtz, the Director of the Division of Neuroscience at the National Institute of Aging (NIA). NIA is a part of the National Institutes of Health (NIH) focusing on age related diseases, such as Alzheimer’s disease. The interview features the past and current research regarding Alzheimer’s disease as well as the future milestones set by the federal government and by NIA.

Alzheimer’s is an irreversible disease that affects the patients’ memory and thinking skills. It is said to be caused by changes that occur in the brain even significantly prior to having the symptoms. These changes include build up of plaques and tangles of proteins beta-amyloid and tau respectively. Research on Alzheimer’s disease has progressed a lot since the 1970s and has several important goals and milestones set for the future.1

PPHR: What are the major accomplishments of Alzheimer’s research so far?

Dr. Buckholtz: In 1906, Dr. Alzheimer, after whom the disease is named, identified the plaques and tangles that are associated with the changes in the brain of people that have Alzheimer’s disease. However, not a lot of research went into the area till probably the mid to late 1970s. Since that time we know a lot more about Alzheimer’s disease research in a number of different areas.

The first area is in terms of the cellular and molecular changes that take place in the brain. This has been studied by looking at both human autopsy tissue as well as various kinds of cellular and animal models of Alzheimer’s disease.

Another area involves the epidemiology of Alzheimer’s disease. This includes the prevalence and incidence, how many people get the disease, as well as the risk factors that are involved in Alzheimer’s disease.

The third area is related to diagnosis. How can you diagnose the disease? There is especially a recent focus on how we can diagnose the disease earlier in the course so that when we do have drugs that can affect the disease modification, we’ll be able to give them to people earlier in the course of the disease and hopefully be able to slow down and stop the disease progression. Eventually our goal is to prevent the disease entirely.

Yet another area has to do with clinical trials. We support several clinical trials which examine various kinds of intervention methods to see if they are useful both for having symptomatic benefits for people who have the disease already and for trying to slow down the course of the disease for people who have Alzheimer’s disease in the earlier stage.

Another area of focus we have is in terms of developing new drugs. So we have a major program on trying to develop and test drugs for Alzheimer’s disease.

I would say that another important area of research is in genetics. We understand some of the genetic risk factors for what we call late onset in Alzheimer’s disease which begins after the age of 60-65 as well as the changes in early onset Alzheimer’s disease due to the inherited form of that occurs in some families.

So I would say that the bottom line is that there has been a lot that has been done in terms of accomplishments in Alzheimer’s disease research especially over the last 20-25 years.

PPHR: What is the future road map of Alzheimer research?

Dr. Buckholtz: In 2011, President Obama signed the National Alzheimers Project Act. Then in 2012, there was a National Alzheimers Plan. Based upon the plan as well a meeting that we held at NIH in 2012, we developed a number of recommendations for future research. There are various kinds of milestones which we have set and the overall goal is to get to a new therapy by 2025. And so that is really the roadmap.

[The National Alzheimer’s Plan has set five primary goals for research and care. It has also provided strategies to accomplish them. The five goals are the following: Prevent and effectively treat Alzheimer’s disease by 2025, Enhance care quality and efficiency, Expand support for people with Alzheimer’s disease and their families, Enhance public awareness and engagement, and Improve data to track progress.3]

That really lays out where we need to go to get to where we want to be in 2025 with the new therapy. That’s an important aspect that happened very recently.

PPHR: We learned that iPS cells (induced pluripotent stem cells) hold promise for potential treatment of Alzheimer’s? How would iPS cells help treat Alzheimer’s?

Dr. Buckholtz: I think at this point we are not sure. Induced pluripotent stem cells (iPS cells) at this point are obviously not ready for therapy. However, they may be useful for therapy development, for screening various potential therapeutic compounds. So if we have aspects of the IPS cells that are similar to what people have in Alzheimer’s disease, such as beta-amyloid, tau, or inflammatory markers, the IPS cells could potentially be used as screeners to identify compounds that could go into further development as therapeutics. They may also be useful for possibly understanding the molecular and cellular aspects of Alzheimer’s disease. But they surely are not ready as therapeutics. And I think that’s kind of where we are.

PPHR: Which are the various methods developed to detect Alzheimer’s? Are there any methods that will help detect the potential for Alzheimer onset in future?

Dr. Buckholtz: First of all, the major way of diagnosing Alzheimer’s disease right now is through clinical and neuropsychological examination which is very useful for people who have symptoms already. What we are very interested in is diagnosing it earlier and earlier in the course of the disease because we know that the brain changes that occur in Alzheimer’s disease start probably 10, 15 even 20 years before the symptoms actually are seen. So we want to understand better what the earliest way is that we can detect these changes in the brain before people develop symptoms. The clinical measures are not quite as useful in picking up these earlier changes, so what we are looking at are biomarkers.

This is really a major area of focus that we are involved in right now. These are ways of looking at the living human brain and identifying the earliest changes that we can pick up. There are a number of different kinds of biomarkers.

The first kinds are the imaging biomarkers. We can use Magnetic Resonance Imaging (MRI) to look at the structure of the brain. We have seen these areas of the brain which seem to change very early in the course of the disease. In these areas, there are cells which are dying and therefore there is shrinkage in these areas of the brain, such as the area called the hippocampus. The hippocampus is in the temporal lobe and it changes very early so we can use MRI to identify hippocampal shrinkage or what we call atrophy. , So that is one way of looking at very early brain changes.

The other kind of imaging is Positron emission tomography (PET) imaging. There are two kinds of PET imaging. One kind measures glucose utilization in the brain as a way of looking at the brain’s use of energy. The brain uses glucose as the major source of energy. In people who have Alzheimer’s disease already, there are very specific areas of the brain where the energy usage goes down. We say that there is a decrease in glucose metabolism. Again by using PET imaging you can pick up these kinds of similar changes early in the course of the disease.

And the other kind of PET imaging that is relatively new and has made a huge change in our understanding of Alzheimer’s disease is the ability to measure beta-amyloid in a living human brain. Beta-amyloid is the major protein involved in Alzheimer’s disease plaques. In Alzheimer’s disease, there are what we know as plaques and tangles. These are the things that Dr. Alzheimers saw under the microscope. The plaques consist of a protein called beta-amyloid and the tangles consist of a protein called tau. Very recently radioactive chemicals have been developed which when given intravenously get to the brain, bind to beta-amyloid, and can thus be measured using PET imaging. So now we are able to actually visualize the amount of beta-amyloid in the living human brain. And again this is something that comes in early in the course of the disease and we are able to look at pre-symptomatic individuals, people who don’t have the symptoms but we can measure that many of them have beta-amyloid in their brains already.

These are ways that we can now look very early in the course of the disease, to look at the earliest changes in the brain before people develop symptoms.

PPHR: What factors would help reduce the risk of Alzheimer’s?

Dr. Buckholtz: Risk factors are factors that increase the risk of Alzheimer’s disease. Just because you have a risk factor does not mean you are going to get Alzheimer’s disease. So these are not determinative factors. But what we know is that things like high blood pressure, obesity, diabetes, cardiovascular factors, and high cholesterol are some of the risk factors. These are things that are treatable that could reduce the risk of Alzheimer’s disease. We don’t know for sure at this point.

However, the major risk factor for Alzheimer’s disease is age. And that’s really the main public health problem with Alzheimer’s disease. We know that the numbers of people over 85 are increasing rapidly and that’s the fastest growing group in the United States. And it is the major age for risk of Alzheimer’s disease. There’s not much we can do about age and age is a major risk factor.

Also there are genes for late onset Alzheimer’s disease that could put people at risk for Alzheimer’s disease. But again at this point we don’t know ways for modifying the genetic risks. On the other hand, I might point that women are at higher risk of having Alzheimer’s disease than men. It has been thought for some time that this is because women live longer than men, but there may be other factors that put women at higher risk for Alzheimer’s disease.

I should also say that there are these drugs which are under development which will hopefully at some point be able to slow down the progression and even prevent Alzheimer’s disease.

PPHR: How is Alzheimer’s treated nowadays? What are future advancements possible in Alzheimer’s treatment in the short run and in the long run?

Dr. Buckholtz: Right now there are only a few drugs that have been approved by the FDA for people who have Alzheimer’s disease already. These provide a symptomatic benefit to people for some time. But again what we are really trying to do is develop new kinds of therapeutics. We obviously need to continue to look for drugs which help people who have the disease already. But a lot of the drugs that are in development and are being tested now are for disease modification that is to hopefully to slow down the course of the disease, to potentially stop the disease at an early stage, and at some point to prevent the disease. That is the main focus of academic research investigators as well as those in pharmaceutical companies.

PPHR: How are undergraduate students/ colleges contributing to Alzheimer’s research?

Dr. Buckholtz: I am not sure how to answer that question. I don’t know if there are specific ways that they are doing it. At academic institutions that have research efforts going on focused on Alzheimer’s disease, students are getting involved in research going on at those institutions and are working with investigators who are involved in various kinds of Alzheimer’s disease research in both basic as well as clinical efforts.

References

1)      National Institute on Aging. Alzheimer’s Disease Fact Sheet | National Institute on Aging. Nov 2013.

2)      Latest Facts & Figures Report | Alzheimer’s Association. Latest Facts & Figures Report | Alzheimer’s Association. Nov 2013.

3)      U.S. Department of Health & Human Services. National Plan to Address Alzheimer’s Disease: 2013 Update. Nov 2013.

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