A conversation with… Dr. Neil Buckholtz

September 30, 2013

Neil BuckholtzDr. Neil Buckholtz is the director of the Division of Neuroscience at the NIA. The Division fosters and supports extramural and collaborative research and training to further the understanding of neural and behavioral processes associated with the aging brain. An important component of the program is the support of basic, clinical, and epidemiological studies of Alzheimer’s disease and related dementias of aging.

Dr. Buckholtz holds a doctorate in physiological psychology from the University of Wisconsin, Madison, and was a faculty member at the Medical University of South Carolina, Department of Psychiatry, from 1970 to 1983. Since joining NIA 23 years ago, he has been a leader in advancing Alzheimer’s research.

Spotlight on Aging Research spoke with Dr. Buckholtz about how the field has evolved during his career, leading to a better understanding of the underlying mechanisms of Alzheimer’s and new tools in detecting the disorder.

Watch a video of the interview with Dr. Buckholtz.

Q: What do you consider the most transformative moments in Alzheimer's research in the past 30 years?

A: Thanks to the dedication of researchers and clinicians determined to find a therapy for this complex and devastating disorder, we’ve come a long way over the past decade or so. While we are still frustrated by the fact that we have yet to find more effective treatments, the field has been tremendously energized by advances in detecting and tracking Alzheimer’s pathology.

One high point was the development of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and its continued success. This is a longitudinal study to look at the best markers or combinations of markers in the brain to assess the changes that eventually lead to the symptoms of the disease. ADNI has evaluated people since 2004 and has been really critical to our understanding of the changes that occur in the brain over time and what comes first in the disease process. We know that these brain changes can begin 5, 10, or 15 years before the symptoms actually develop.

Q: What do you consider key to the success of ADNI?

A: I think a real breakthrough—and I almost never use that word—came in 2004 with the development of Pittsburgh compound B. This is a chemical that binds to beta-amyloid in the brain so that the amount of beta-amyloid can be assessed using PET scans in living people. So, now we can use MRI imaging to look at brain structure over time and PET scans to detect and track the levels of beta-amyloid in the brain over time.

This breakthrough has transformed our understanding of the very earliest changes that occur in Alzheimer's disease, and it’s been critical to the development of new therapeutics that target beta-amyloid. And now, work is underway on new PET chemicals that will allow us to look at tau in the living brain.

Another big evolution in the field is the widespread collaboration among researchers, with the sharing of data soon after it is obtained. ADNI study data, for example, are posted to a publicly accessible database available to qualified researchers worldwide. To date, more than 2,200 researchers have signed up for ADNI database access. ADNI is stimulating the development of a worldwide collaboration among academia, government, and industry researchers and has resulted in more than 350 published papers.

Collaboration has also been key to recent advances achieved by genome-wide association studies. I think everyone personally touched by Alzheimer’s—from researchers to clinicians to those generous volunteers and their families participating in studies—share a deep appreciation that we must work together to reach our end goal of finding effective therapies.

Q: Is this commitment reflected on a national level?

A: Most definitely, and this, too, is reason for optimism. In 2012, Health and Human Services Secretary Kathleen Sebelius announced the National Plan to Address Alzheimer's Disease. One focus of the Plan, the one aimed at research, is to develop new ways to prevent or treat Alzheimer's disease by 2025. It not only calls for the testing of effective therapies for people who currently have Alzheimer's—and in the United States this may be as many as 5 million people—but also focuses on trying to change the course of the disease, by slowing down disease progression. And eventually, we hope to be able to delay the onset or prevent Alzheimer's disease entirely. The new national push on Alzheimer’s has re-energized all of us, I think, and has elevated research on Alzheimer’s in the national conversation about aging and health.

Q: What are some promising areas of research that may help us reach these goals?

A: A number of areas are advancing our understanding of Alzheimer's disease. One of these is biomarkers to assess the pathophysiological changes that occur in the living human brain long before symptoms appear. We have ways of assessing beta amyloid, using PET scans, and there are new chemicals that are going to allow us to assess tau. There are biomarkers in blood and cerebrospinal fluid that can be measured. And again, these changes occur many years before the clinical symptoms. So this has been a major advance in our ability to assess people, what we call pre-symptomatically or pre-clinically, before the symptoms of Alzheimer's disease develop.

Another advance has been in the area of genetics and genomics. We’ve known for some time that there are three mutated genes that lead to dominantly inherited, early-onset Alzheimer’s disease. In families with these genes, people get Alzheimer's disease in their 30s, 40s, and 50s. However, there are also a number of risk factor genes for late-onset Alzheimer's disease, which occurs after about the age of 60 or 65. So if you have one or more of these risk factor genes, your risk of developing Alzheimer's disease is increased, but it doesn’t mean that you're actually going to get the disease.

One gene that we’ve known about for 20 years is APOE ε4. But now, through genome wide association studies as well as whole genome sequencing studies, we’ve identified other risk factor genes for late-onset Alzheimer's disease. We’re trying to understand how these genes interact with each other, how they interact with the environment, and how they may provide us with leads for development of new therapeutics or interventions.

Our Alzheimer's disease clinical trials also offer hope. Currently approved treatments provide symptomatic benefit to people who already have Alzheimer's disease. However, what we really want to do is to be able to prevent it, or delay its onset and delay disease progression. So the clinical trials that are starting now and will be starting over the next year or two are really focused on the pre-clinical or pre-symptomatic stage of the disease where treatment might be most effective. We can now identify people in the pre-symptomatic stages who are at high risk for developing Alzheimer’s with the use of biomarkers in cerebral spinal fluid and by the use of various kinds of imaging. Hopefully, some of these drugs that are being tested will actually be able to delay the disease progression or eventually delay the onset of disease.

Q: What are the greatest challenges faced by researchers in this field?

A: Funding, especially in this economic climate, is definitely a challenge for the research community. We are committed to working smarter, to finding ways to leverage our resources, and to looking at new ways to do things. Collaboration and open accessibility to data, of course, are vital to making the most of our available resources.

We also need to better understand the pathophysiological changes that occur in the brains of people who will eventually develop the symptoms of Alzheimer's disease. Since 1906, when Alois Alzheimer described the brain of a woman who died of what we now call Alzheimer's disease, we’ve known about plaques and tangles. And in the 1970s and 1980s, the proteins that are involved in development of these plaques and tangles were identified—beta-amyloid for plaques and tau for tangles.

But we now understand that there are a lot of other things going on in the brains of people with Alzheimer's disease. For example, we know that inflammation occurs. What we don’t know is whether inflammation is an initiating event or is a consequence of the development of other pathologies, such as the plaques and tangles. There are synaptic changes that occur. There’s also the death of nerve cells in the brain. All of these things are changing over time. The hope is that by understanding these changes, we’ll have better targets for developing new therapeutics for Alzheimer's disease.

Q: With funding at a premium, how do you allocate our research resources?

A: The International Alzheimer’s Disease Research Portfolio (IADRP) is one way to assess the research on Alzheimer's disease that’s funded not only by the National Institutes of Health but by other government agencies, such as the Veterans Administration and the Centers for Disease Control and Prevention, as well as non-government organizations like the Alzheimer's Association. The freely accessible database, a collaborative effort between NIA and the Alzheimer’s Association, also incorporates funders based in other countries. So, you can search various categories to look at what is being funded over time.

For example, we know that preclinical Alzheimer's disease drug discovery has changed with respect to the proportion of grants that focus on beta-amyloid versus non-beta-amyloid targets. IADRP gives you a better idea of how the funding is changing over time and what exactly is being funded internationally.

Q: You recently attended the Alzheimer’s Association International Conference in Boston. Were there any studies or findings that you found particularly significant?

A: If I had to pick just one, I’d share that I was very intrigued by the idea of subjective cognitive impairment. We’ve known for some time that many people think that their memory is getting worse, but it hasn't been really clear if this is a harbinger of Alzheimer's disease or just something that people believe that really doesn’t have a major effect on the development of the disorder.

However, at the meeting, a number of studies were presented that indicated that when people believe that their memory is getting worse and this is corroborated by someone else—their spouse, a friend, somebody like that—then actually there may be an increased risk of subsequent development of Alzheimer's disease. I think that this is going to be looked at much more with respect to trying to understand the phenomenon, as well as trying to see if we can pick up brain changes that are related to this subjective cognitive impairment.

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