When molecular biologist Darren Baker was winding up his postdoc studying cancer and aging a few years ago at the Mayo Clinic in Rochester, Minnesota, he faced dispiritingly low odds of winning a National Cancer Institute grant to launch his own lab. A seemingly unlikely area, however, beckoned: Alzheimer's disease. The U.S. government had begun to ramp up research spending on the neurodegenerative condition, which is the sixth-leading cause of death in the United States and will afflict an estimated 14 million people in this country by 2050. "There was an incentive to do some exploratory work," Baker recalls.
Baker's postdoc studies had focused on cellular senescence, the cellular version of aging, which had not yet been linked to Alzheimer's. But when he gave a drug that kills senescent cells to mice genetically engineered to develop an Alzheimer's-like illness, the animals suffered less memory loss and fewer of the brain changes that are hallmarks of the disease. Last year, those data helped Baker win his first independent National Institutes of Health (NIH) research grant—not from NIH's National Cancer Institute, which he once expected to rely on, but from the National Institute on Aging (NIA) in Bethesda, Maryland. He now has a six-person lab at the Mayo Clinic, working on senescence and Alzheimer's.
Baker is the kind of newcomer NIH hoped to attract with its recent Alzheimer's funding bonanza. For years, patient advocates have pointed to the growing toll and burgeoning costs of Alzheimer's as the U.S. population ages. Spurred by those projections and a controversial national goal to effectively treat the disease by 2025, Congress has over 3 years tripled NIH's annual budget for Alzheimer's and related dementias, to $1.9 billion. The growth spurt isn't over: Two draft 2019 spending bills for NIH would bring the total to $2.3 billion—more than 5% of NIH's overall budget.
Such a dramatic increase in research funding for a disease has no precedent at NIH aside from the War on Cancer, an effort launched in 1971, and an explosion of AIDS funding in the late 1980s. With the largesse come logistical challenges. Overworked NIH staff are scrambling to review and process thousands of grant proposals, including those for this year's $414 million bolus—a sum that equals the entire budget of some smaller NIH institutes—which Congress approved in March.
NIA, which oversees the new funds, doesn't just want to plump up existing Alzheimer's labs, says Director Richard Hodes. The institute is also luring investigators, such as Baker, from other fields to bring in fresh ideas. Many are answering the call. "Nearly everyone I know is putting the words ‘Alzheimer's disease’ in their grants in an effort to tap into the money," says Matt Kaeberlein of the University of Washington in Seattle, who studies aging.
The funding blitz targets a problem that looks more intractable than ever. The only approved drugs for Alzheimer's don't stop the neurodegeneration, but merely treat symptoms—and not very well. In the past year, several major clinical trials based on the field's leading hypothesis—that reducing the level of β-amyloid plaques that riddle the brains of Alzheimer's patients would halt disease progression—have flopped. An antibody that targets β-amyloid recently delivered seemingly promising results in a phase II trial. Yet given past failures for other eagerly watched compounds, many researchers remain skeptical and want to see a larger phase III trial.
Nearly everyone I know is putting the words ‘Alzheimer’s disease’ in their grants in an effort to tap into the money.
Those setbacks have amplified concerns that U.S. officials and some scientists have oversold the plan for a treatment by the middle of the next decade. "I am convinced that we are destined to fail to make the 2025 goal and therefore look like we have failed at our promise," says Alzheimer's researcher Samuel Gandy of the Icahn School of Medicine at Mount Sinai in New York City. Some researchers also worry about focusing so much money on just Alzheimer's. The biomedical community "has mixed feelings" about such targeted funding, says biogerontologist Judy Campisi of the Buck Institute for Research on Aging in Novato, California, who wonders whether more should go to basic research.
Even Baker has qualms. "I think it is great that there's all of this funding. I just hope it's not at the expense of something interesting in the cancer realm."
But naysayers are few. "Overall, what is wrong with it? Nothing," says biochemist Rozalyn Anderson of the University of Wisconsin in Madison, who studies caloric restriction in monkeys to slow aging and is now tying that work to Alzheimer's. "It's a great experiment underway: By increasing funding and access to resources, can we bring on a game-changer in research in a particular area?"
A "confluence of factors" unleashed the funding surge, says Sue Peschin, president and CEO of the Alliance for Aging Research in Washington, D.C. Families became more open about the once-hidden disease, and advocates became savvier. In the late 1990s, the Alzheimer's Association in Chicago, Illinois, and later other groups began to frame care for Alzheimer's patients as a financial crisis looming as the large baby boomer population ages. Alzheimer's already costs Medicare and Medicaid $186 billion per year, and the figure will balloon to $750 billion by 2050, according to the Alzheimer's Association.
Advocates also argued that Alzheimer's is underfunded in the United States in comparison with major killers such as cancer and heart disease. That's especially true for AIDS, which until recently received a fixed 10% of NIH's overall budget—it now gets $3 billion per year—yet affects far fewer Americans. "Neurodegenerative diseases have historically never really had the same funding. In a sense this is a correction," says Alzheimer's researcher John Hardy of University College London.
Those messages resonated with U.S. lawmakers, including Senator Susan Collins (R–ME) and then-Representative (now Senator) Edward Markey (D–MA), who in 1999 co-founded the Congressional Task Force on Alzheimer's Disease. In 2011, they co-sponsored the National Alzheimer's Project Act, which called for a U.S. plan to improve research and care for people with Alzheimer's and related dementias. After Congress passed the bill, the Department of Health and Human Services (HHS), NIH's parent department, outlined ambitious goals, the most striking being to "prevent and effectively treat Alzheimer's disease by 2025." Some Alzheimer's researchers had misgivings about the deadline, says David Holtzman of Washington University School of Medicine in St. Louis, Missouri: "I don't think most thought it was realistic."
The Mayo Clinic's Ronald Petersen, who chaired the advisory board that drafted the HHS plan, defends the 2025 goal: "We wanted to make a bold statement. Not ‘We hoped to make progress.’ That isn't going to inspire anybody."
As more lawmakers joined the cause, Congress in 2015 mandated that NIH prepare a "professional judgment" budget on Alzheimer's research, a wish list of needs to meet the 2025 target that would bypass the federal budget process and go directly to the president and Congress. Until then, only cancer and AIDS had enjoyed that special treatment. Alzheimer's advocates also lobbied the administration of former President Barack Obama to include extra funding in the White House budget request, Peschin says.
The lobbying began to pay off as early as 2012 when then–HHS Secretary Kathleen Sebelius held a press conference to announce modest increases in funding for Alzheimer's research. That gained the attention of some scientists, including Baker, who submitted his grant proposal to NIA in 2015. However, the big ramp up began only in 2016 after Obama and lawmakers struck a deal to lift federal spending caps and Congress boosted NIH's overall budget after a decade of stagnation. That fiscal year, the share of NIH money going to Alzheimer's shot up 56% to $986 million, including $57 million for separate research on three related dementias, such as vascular dementia. By now, 3 years of such funding boosts have transformed NIA—once a midsize NIH institute and "almost a backwater," as one official put it on a blog—to the fifth-largest of NIH's 27 institutes and centers with a $2.6 billion overall budget. "Our continued investment will pay dividends for the millions of families affected by Alzheimer's," Collins said in a statement to Science.
The windfall is incredible, says Eliezer Masliah, director of NIA's Division of Neuroscience. "I've been in this field for over 30 years, and I've never seen anything like this. This is really a golden era for [studying] Alzheimer's disease."
Now, the onus is on NIA and the research community not to waste the money. Under the national plan, NIH holds summits every 3 years to guide its Alzheimer's efforts, targeting the most promising lines of research. Some 140 treatment or prevention trials are underway, testing both drugs and preventive interventions such as exercise. The funding has supported a consortium working on novel mouse models, genetically engineered to mimic the common, late-onset form of the disease. Other money goes to modeling the disease by editing Alzheimer's risk genes in neural cells derived from stem cells.
Basic researchers are exploring new hypotheses. Some of NIA's recent funding opportunities invite research on alternatives to the long-dominant idea that β-amyloid deposits outside brain cells and "tangles" of the protein tau inside neurons are the key drivers of Alzheimer's disease and the best treatment targets. The announcements call for proposals in less-explored areas, such as the role of protective genes, how neurodegeneration affects other animal species, and how metabolic changes might contribute to Alzheimer's. "This brought in many people who were reluctant to submit an Alzheimer's application in part because they thought, ‘We're never going to do well, we're going to be outsiders,’" Hodes says. At a recent Senate hearing, he pointed out that of 452 investigators who won new Alzheimer's and related dementia grants from 2015 to 2017, 27% were receiving their first independent NIH grant, like Baker, and 36% were established researchers who had never had NIH support for Alzheimer's. (Some had funding from Alzheimer's foundations, however.) "We're not just repeating the things that failed and hoping we get a different result," Hodes says.
Masliah says that compared with a few years ago, when less than half of NIH's portfolio in Alzheimer's was devoted to areas other than β-amyloid or tau, it's now more than 60% for translational studies and about 70% for basic research. "I do believe there is more money available for us to explore these other ideas," says Carol Colton of Duke University in Durham, North Carolina, who studies inflammation as a possible cause of Alzheimer's. She and others add, however, that the academics called on to review NIH grant proposals are sometimes less open-minded than NIA staff and nix proposals in new areas. They "need to catch up," Colton says.
To cast an even wider net, NIA is offering 1-year funding supplements to researchers already funded by NIH in other areas who want to add an Alzheimer's component to their research. The hope is that the extra money will lead to full-fledged proposals.
Alzheimer's grants are now much easier to get than other NIA grants: For most Alzheimer's proposals this year, those ranked in the top 28th percentile by peer-review panels get money. For non-Alzheimer's grants, that pay line is the 19th percentile. The competition for grants is still stiff, Hodes stresses. After all, he notes, high-quality applications for the Alzheimer's pool of money have "increased dramatically" in the last couple years "as word got out."
NIA grantees in fields with scarcer funding aren't complaining, so far. Some recipients even suggest they're benefiting because competitors in the field of aging are shifting into Alzheimer's. "Paradoxically, the new funding injection could improve everyone's chances of funding," says Duke psychologist Terrie Moffitt, a member of NIA's advisory council.
NIA has had to be creative to cope with the tide of applications for the Alzheimer's bounty, agency officials say. After a crushing scramble to process grant proposals last summer, this year NIA called early for proposals and scheduled peer-review panels even before it knew its final 2018 budget. Adding to the pressure, President Donald Trump's administration imposed a federal hiring freeze last year that was only recently lifted at NIH. "I think our staff has managed heroically to still be doing an extremely conscientious job. … Where we've compromised probably is the quality of life of a lot of our staff," Hodes says.
At the NIH Center for Scientific Review in Bethesda, which arranges peer-review panels for much of the funding, "We're handling the load as best we can," says acting Director Noni Byrnes. The pool of potential reviewers—U.S. Alzheimer's researchers who aren't applying for the new funding themselves and so don't have a conflict of interest—is limited. So, for NIA-organized review panels, the institute is also using Alzheimer's experts in Canada and Europe, says Ramesh Vemuri, NIA's chief of scientific review.
Clinical trials won't be easy to staff either. Clinical researchers and neuropathologists focused on dementia are in short supply, says Alzheimer's Association Chief Science Officer Maria Carrillo. NIA is trying to attract them by funding fellowships. Another huge problem is finding enough subjects for trials—especially those who are at high risk for the disease but still without symptoms, the population on which some researchers think amyloid-busting drugs could yet work. NIA plans to launch a national recruitment strategy that includes raising awareness about trials.
Looming over the massive research push is the 2025 goal. It was set when optimism ran high that drug trials based on the β-amyloid hypothesis would pan out, Carrillo and others say. But if patients must begin antiamyloid treatments well before symptoms set in, seeing clinical benefits could take decades, Gandy notes. And the chances of meeting the deadline by targeting a different disease mechanism are small; such treatments remain far off. Still, Holtzman hopes for good news from an antiamyloid treatment trial. "Something is likely to be approved by 2025. It won't be the be all, end all," he says, but he hopes it will keep everyone motivated. "Because we don't just need money from the NIH, we need the pharmaceutical industry to not drop out"—as Pfizer did this year when it announced it was abandoning Alzheimer's research.
Some researchers point to the mixed success of NIH's other disease "wars": AIDS funding hasn't led to a cure or a vaccine, though it has yielded drugs that allow people infected with HIV to lead nearly normal lives. The war on cancer has led to treatments that are improving survival, but cancer remains the second-leading cause of death in the United States.
That history makes former NIH Director Harold Varmus cautious about the 2025 goal. "No one denies the enormous need to make progress against Alzheimer's," he says. But, "I wish a date were not attached."
Hodes concedes that, like real wars, disease wars can last far longer than anyone imagined—or feared. But that doesn't mean it was a mistake to launch an all-out offensive against Alzheimer's disease, he says. "If 2025 comes and we haven't achieved all we wanted, I'm not going to stop there and declare failure."