After a career spent in Mexico and California, this past July Eliezer Masliah gave up Pacific sunsets for a new gig on the East coast. Best known for his research on synaptic damage and on poly-proteinopathies involving α-synuclein, Masliah left the University of California, San Diego, to take over the director’s chair of the National Institute on Aging Division of Neuroscience. He replaced Neil Buckholtz, who had retired last December, and, more recently, Tony Phelps, who led the division in the interim (see NIH press release). What is Masliah’s vision for the field, and the division’s role in AD research? Questions by Gabrielle Strobel.
First off, what does the director of the NIA’s Division of Neuroscience do?
I am responsible for the Alzheimer’s disease portfolio funded by NIA. This includes all basic science related to AD, all special programs such as the AD centers, the National Alzheimer’s Coordinating Center (NACC), the Alzheimer’s Disease Genetics Consortium (ADGC), the clinical trials centers (ADCS), ADNI; in short, all the initiatives for AD as well as the science. Add to that responsibility for the new funding for AD in response to the National Alzheimer’s Project Act (NAPA). The National Plan that grew out of NAPA has to be updated every year with special calls for funding in response to the AD and Alzheimer’s Disease-Related Diseases (ADRD) summits that we host. These calls are milestone-driven and are responsive to the community’s recommendations on how to advance AD science to reach the goal of better treatments for AD by 2025. All of that is under my umbrella.
The NIA has four extramural divisions: Besides Neurosciences, there are Aging Biology (DAB), Geriatrics and Clinical Gerontology (DGCG), and Behavioral and Social Research (DBSR). Do the other divisions handle AD, too?
Yes. Neurosciences does that primarily but we also interact with other divisions, mostly with DGCG and DBSR. We are expanding collaborations with DAB. Neuroscience is the biggest division, with about two-thirds of the budget.
How does your work relate to that of NIA colleagues with whom our audience already interacts? Tony Phelps, Laurie Ryan, Richard Hodes, many others?
I work under the direction of Richard Hodes. Tony Phelps, Laurie Ryan, and others work under my leadership. Tony is deputy director of the division of neuroscience; Laurie, Brad Wise, and Molly Wagster are our division’s branch chiefs for the Dementias of Aging, Neurobiology of Aging, and Behavioral and Systems Neuroscience branches, respectively. Within those branches, we have program officers the Alzforum audience knows, such as Dallas Anderson, Suzana Petanceska, Larry Refolo, Nina Silverberg, Austin Yang, and others. (For a full list, see NIA Division of Neuroscience webpage.)
NIA had good news in the form of an additional $350 million. Explain?
The first $350 million additional money was allocated for FY 2016; of that, a chunk has already been spent on grants that came in response to 2016 funding opportunity announcements (FOA, aka RFA). We issued 10 FOAs in 2016, of which seven were specifically on AD and three on ADRDs in collaboration with NINDS. Applications were submitted in response to this in October 2015 and a number of those are approved. These FOAs were in response to the science recommendations from the AD and ADRD summits up to then.
We will get hopefully this same additional amount again in 2017 for FY 2018. Traditionally, the budget of the NIA Division of Neuroscience has been in the neighborhood of $500 million. We were stuck there for many years. Then came the added $350 million, which we will continue to get, so that our base budget from now on will stand at $850 million. Plus we are expecting another $340 million on top of that.
I call this the golden era of Alzheimer’s disease research. This is a real shift. We will talk about the NIA pre-NAPA and post-NAPA. It is a different ballgame now. I hope your readers will get the feeling that there has been a dramatic historical change in thinking and funding. Often people are skeptical about politicians having big ideas but attaching no funding to them. Now there is funding. This is real.
What will you do with this money?
Its spending is totally driven by the recommendations of the investigator community. That is very important for the Alzforum audience to understand. A few new RFAs are already published for 2017 that reflect these recommendations. For example, there is more funding on pathogenesis of AD using new cellular models such as iPSCs. People want more basic research in the “omics” era. There is more funding to translate new genetic findings of AD to understand basic mechanisms, and to develop new, more reproducible animal models. There is more money for clinical trials, devices for monitoring, there is money for a centralized digital IRB, many other topics.
This is a big process. Can you continue your personal research interests?
No. I had to put them aside. I gave up all my grants, contracts, the cores, program projects. I dissolved my lab. I am fully committed to this effort. It is a historical moment.
No nostalgia, no second thoughts?
No. It is unrealistic to try to do this job anything less than full time.
What will you focus on in your first year; what are your longer-terms goals?
First, I want to get to know better the needs of the division, and build relationships with the other divisions and other NIH institutes to synergize and enhance collaborations. I will talk more with the scientific community and bring the division closer to them.
We also need to do work internally. With the new funding, the division has to grow, reorganize along the lines of new needs, and hire new people. My job is to provide leadership as we organize new programs in response to the summits and milestones of NAPA.
One big area of concern is patient recruitment. I want to work more closely with people in the field to help increase patient enrollment into ADNI and clinical trials.
On that, do you see your role as working with clinical investigators and sites via the NIA’s AD centers program? Or with outside groups that make recruitment their calling card, such as existing registries, the GAP Foundation and their Kansas City pilot, and other types of outreach?
All of the above. We can work with these groups to facilitate their efforts, to get the ADCs informed and on board, and to boost capacity at the centers to handle increased recruitment. The centers program just grew, incidentally, with the addition of the Michigan Alzheimer’s Disease Core Center in Ann Arbor, led by Henry Paulson, and the Wake Forest Alzheimer’s Disease Core Center in Winston-Salem, led by Suzanne Craft. (Editor's note: See NIA press release.)
I often hear how solving neurodegeneration is too large for a lab, a pharma company, even a country. There is momentum in expanding collaboration, especially for human genetics, biomarker, and clinical studies that require very large cohorts. What can you do to aid international collaboration?
We have started communications. Similar to the National Plan in the U.S., many European countries have already initiated national efforts. There is an AD initiative in the U.K. right now, and there has been one in Germany for several years. Also in Japan, France, Australia, and other places in the world. Our primary point of contact is each country’s equivalent of its national plan to address AD, and we are communicating with them so we can become more familiar with each other’s programs. I’d like to find ways to synergize and collaborate.
In Europe, for example, a large funding body is the Joint Programme for Neurodegenerative Disease Research (JPND). Their calls for applications require collaboration built into the structure of the proposal. Typically that involves several different European countries. Could NIA work with foreign government funders such as JPND to pool funds to achieve larger international goals? If so, how?
We absolutely want to explore avenues to collaborate with JPND. We want to figure out how we can harmonize the way we fund, but it’s too early to comment on that in any detail.
For a while, some investigators in the AD field grumbled that large grants to clinical trials were drying up funds for individual labs.
That is a misperception. It exists because those large grants are high profile. Of NIA funding, 75 percent supports basic pathogenesis and RO1 types of grants. The centers and trials take a smaller proportion. Personally, I come from basic pathogenesis and am very interested in seeing RO1s for basic science continue, balanced with grants for trials.
You say the NIA is more than “just” a funding agency. In what way?
This is important. True, there is now much more money, but the reality is the money goes to two things. One is to grants. The other is resources. NIA is a fantastic resource for any investigator, and I hope Alzforum readers will explore those. When I started in research 30 years ago, there were no resources. There were brains in buckets, that was it. Now, you can go to the NIA website and see all the resources the institute is giving to the community. It is fantastic. There is ADNI, the AD centers, the research portfolio database, IADRP, more. There is all this data. You could do research just mining NIA data. For me it’s important to think about that balance of funding for research and funding for shared resources so the community can collaborate better.
Despite progress in the last 10 years the AD field is still marked by classification debates, and I sometimes hear that they are holding the field back. Some people view dementia as a multifactorial clinical syndrome and prioritize research on the mixed dementia that is so often evident at autopsy. Other people delineate specific underlying proteopathies and say different people with dementia symptoms have different diseases depending on what causative protein drives their symptoms. Yet others point to the cerebrovasculature. Those different perspectives have consequences for research priorities. Where do we have most to gain?
You are raising the concept of heterogeneity of Alzheimer’s disease and its characteristic etiology. We issued an FOA among the 2016 group of 10 that is asking for research to address that very question. That will be a recurring theme. It is clear that AD is not a one- or two-protein disorder but a poly-proteinopathy. We do not know much yet about the role of α-synuclein, TDP-43, and TREM2 in AD and the ADRDs. Those need to be more investigated.
For example, when I am talking about the role of α-synuclein in AD, I do not mean dementia with Lewy bodies (DLB). I am really talking about pure AD, where half of all cases have a lot of Lewy pathology. What does it do? We know so little. Likewise, with TDP-43 I am not talking about FTD, but pure AD. We know little about it there.
We have learned in the last few years that the older a person is at symptom onset, the more mixed and heterogeneous is their disease and the more important vascular factors become. The younger the onset, the more straightforward is their disease; you find plaques, tangles, maybe α-synuclein and subtle cerebrovascular abnormalities, period. Classifying disease by age of onset may help.
Another way is gender. There are some differences in how AD presents in men and women, and that needs to be investigated.
A third one is genetics of course. AD is a polygenetic disorder, whose genetics varies between populations by gender, ethnicity, and age of onset.
As we develop more lifetime biomarkers for Aβ, tau, α-synuclein, TDP-43, and other pathogenic proteins, does it make sense to name an individual person’s disease accordingly? Will we carry what we learned from basic pathophysiology into the diagnostic process and clinical language?
Because both the health care system and life expectancy are expanding, we are seeing older and older patients who are developing a broad spectrum of dementia. So yes, we have to use biomarkers broadly. Right now, based on autopsies we assume that most TDP-43 in AD comes up after Aβ and tau, but what if once we have imaging tools for α-synuclein and TDP-43 we see it come up earlier, in the 40s or 50s? So yes, once we have more biomarkers, that information might completely change our view of the disease.
With vascular changes it is same thing: Right now with the best MRI and imaging tools, we can only detect certain types of vascular disease, and yet the kind we see in older people are tiny microinfarcts that we often miss. What about once we come up with a better imaging technique and start seeing those things earlier? Absolutely, that could change the way we think about these diseases, and what we call them.
So once we have more biomarkers, and have used them longitudinally for a meaningful observation period, we may be able to characterize a given person’s disease as the sum or the order of their component proteopathies?
Absolutely. That will help move diagnoses from a descriptive clinical phenotype to a molecular footing. This, in turn, will help with personalized medicine and therapeutics. In the case of Aβ, we know thanks to imaging that it accumulates rapidly very early, even preclinically, so we know we have to target Aβ at that stage. We know tau changes later, so we know where the window to target tau is. As we learn more about TDP-43 and inflammatory processes, we will know when are their windows of opportunity for therapy. There is a strong effort at NIH, with a funding initiative, on personalized medicine.
I sometimes hear the funding crunch of the past years has led to a dearth of young investigators, and now that the field is wanting to expand fast, they are not there. Do you agree?
No. I agree that a lot of people shied away because of the period of decreasing funding, but I still see tremendous interest out there. One focus for our new money is to fund more young people. We will need more basic scientists, clinicians, neuropathologists, neuropsychologists.
A final word to the Alzforum audience?
Because NIA funding is community-driven and informed by the summit, I encourage people to participate at all levels of this process. Come to, or stream, the summit. Comment, submit proposals. Take advantage of all granting mechanisms, not just RO1s. Review the training grants, the career development (K) awards, etc. In particular, we’d like to see more applications from the private side, more SBIR, STTR, and Blueprint grants.
Thank you for this conversation.
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