The National Institutes of Health announced September 18 that it will allocate $45 million in new funding to advance Alzheimer’s research. The bulk of the money will help support therapeutic prevention trials in cognitively healthy populations at high risk of developing AD. Smaller awards will fund translational research that will identify new therapeutic targets by constructing network models of AD using human data. The funding follows recommendations made at the 2012 NIH Alzheimer’s Disease Research Summit and contribute to the research milestones of the National Plan to Address Alzheimer’s Disease. Under this plan, in 2012 the government gave $50 million in new funding to AD research. The new awards bring the total to $95 million. Previously, the government had requested $80 million for 2013, which did not materialize (see ARF related news story). Other diseases receive much more, with $5 billion per year going to the National Cancer Institute, for example.

Early and Preventive Trials: Can They Slow Progression?
The largest award, at $33.2 million, goes to the Alzheimer’s Prevention Initiative's ApoE4 Trial. The API's co-PIs are Eric Reiman and Pierre Tariot at the Banner Alzheimer’s Institute, Phoenix, Arizona, and Jessica Langbaum there helps lead the effort. The API will test whether an anti-amyloid therapy can slow cognitive decline in 650 cognitively healthy people between 60 and 75 years old. All participants will have two copies of the ApoE4 allele, putting them at high risk of developing AD. The five-year trial is expected to cost well more than $100 million total, with additional funds coming from philanthropy, while the lion’s share will be provided by a pharmaceutical partner, Reiman said. Researchers are still selecting the industry partner and the drug for the trial. The trial, which has a planned start date of early 2015, is intended to support FDA registration of a successful drug.

In addition to testing a specific therapeutic—and testing the amyloid hypothesis itself—the trial will offer other benefits to the AD field, Reiman told Alzforum. Researchers will look at a suite of imaging and fluid biomarkers to find those that track with cognitive outcomes and might serve as surrogate endpoints, potentially allowing future prevention trials to be shorter. All data and biological samples from the study will be made publicly available to other researchers. The trial will also investigate the impact of revealing ApoE genotype to participants. Previously, the REVEAL study led by Robert Green and Lindsay Farrer at Boston University Medical Center in Boston, Massachusetts, found little negative effect from informing a select population of middle-aged people of their ApoE status (see ARF related news story). “The idea is to extend that elegant work and figure out what the impact is in people who are a little bit older and homozygous, and to see how the impact of disclosure changes over time. Now that there are prevention trial opportunities, the risk-benefit ratio may change,” Reiman noted. Jason Karlawish from the University of Pennsylvania, Philadelphia, leads this part of the trial.

The ApoE4 study complements API’s other prevention trial in a Colombian kindred with an inherited form of AD due to the Paisa mutation in presenilin-1. On track to start this fall, that 300-person trial will test whether Genentech’s antibody crenezumab can delay symptoms in mutation carriers. In 2012, the Colombian trial received $16 million in funding from NIH as part of the national plan (see ARF related news story). Like the ApoE4 trial, this $100 million trial receives most of its support from industry and philanthropy.

In addition to API, the new NIH funding supports another large prevention initiative, the Dominantly Inherited Alzheimer Network (DIAN), led by Randall Bateman and colleagues at Washington University in St. Louis, Missouri (see ARF related news story). The DIAN prevention trial will receive $1.5 million per year for four years, rounding out funding from the Alzheimer’s Association and pharmaceutical partners. Its biomarker portion is now fully funded, Bateman told Alzforum, but the cost of administering cognitive tests to participants, as well as additional planned biomarker studies, are not (see ARF related news story).

DIAN’s four-year prevention trial in AD mutation carriers is currently enrolling participants. Initially, the trial will test the antibodies gantenerumab and solanezumab in separate arms. The researchers are evaluating additional drugs to add to the study. The trial is evolving toward an adaptive design, where multiple drugs can enter the biomarker part of the trial for evaluation, Bateman told Alzforum. He noted that the NIH support is essential for this effort and will ultimately help the whole field. “A huge benefit of these trials is that we’ll be able to make results and samples publicly available to researchers to advance the fight against Alzheimer’s,” he said.

A third large prevention initiative, the Anti-Amyloid in Asymptomatic Alzheimer’s Disease (A4) Trial, will test solanezumab in cognitively healthy people with biomarker evidence of AD. A4 was previously funded through an NIH award to the Alzheimer’s Disease Cooperative Study (see ARF related news story, ARF related news story).

In addition to these prevention studies, the NIH awarded $2.4 million to support a Phase 1 trial of the neurosteroid allopregnanolone. Co-Principal investigators Roberta Brinton and Lon Schneider of the University of Southern California, Los Angeles, will test the drug’s safety and tolerability in 32 people with mild cognitive impairment or early AD (see ARF related news story). Animal studies suggest that this drug stimulates the birth of new neurons, rescues cognition and lowers pathology.

“This is a novel and interesting approach, with strong preclinical support,” Paul Aisen at the University of California, San Diego, wrote to Alzforum. He is not involved in the work.

Harnessing Computational Methods to Find New Targets

Many researchers believe that a better understanding of the mechanisms of Alzheimer’s disease will be essential to find the best targets for therapy. Participants in the NIH AD Research Summit recommended using network-based approaches to integrate large-scale multidimensional human data to disentangle the complex biology of this heterogeneous disease, said Suzana Petanceska, a program director at the National Institute on Aging. To this end, NIH funded three separate but complementary studies that take this approach. Each approach starts with human data, applies different computational methods to extract insights about disease mechanisms, and then builds predictive models of the disease that can be experimentally tested, Petanceska said. Test results will feed back and refine the model, and help predict how a particular target will behave when modulated therapeutically. The idea is that researchers will then use this data to identify existing drugs that may help normalize dysfunctional networks. “These studies will inform drug discovery and put it on a solid footing for success,” Petanceska said. Researchers discussed this approach in a recent Alzforum webinar (see Live Discussion).

Other researchers praised the strategy. “Alzheimer's disease could benefit from fresh approaches such as this to help to identify biological pathways and targets beyond those that have inspired drug discovery related to amyloid and tau,” Doug Galasko at UC San Diego wrote to Alzforum (see full comment below).

In one such study, Philip De Jager at Brigham and Women’s Hospital, Boston, and David Bennett at Rush University Medical Center, Chicago, will lead an interdisciplinary team that will analyze existing clinical, pathological, and genomic data from more than 1,000 participants in the Religious Order Study and the Rush Memory and Aging Project. They will look for genes and molecular networks that influence cognitive decline and test these candidates in cellular model systems. Then they will look for drugs that have completed at least Phase 1 safety studies to find those that restore normal function.

By contrast, a team led by Eric Schadt and colleagues at Mount Sinai School of Medicine, New York City, will generate new human data by analyzing gene expression from hundreds of banked AD brains across all stages of the disease. The researchers will use expression and genomic data to construct global maps of disease genes, which they will validate in cellular and animal models. Then they will apply a computational approach that will allow them to identify whether any existing drugs can normalize these perturbed networks.

Meanwhile, researchers led by Todd Golde at the University of Florida, Gainesville, will focus on the innate immune system, which in the brain is mostly mediated by microglia. Recent studies have implicated several microglial receptors in AD (see ARF related news story; ARF related news story; ARF related news story; ARF related news story). Inflammation seems to play a key role in exacerbating AD pathogenesis (see ARF webinar). “This area is a gold mine for potential therapeutic targets based on what we know from genetics and pathology,” Petanceska said. The team will analyze genomic, gene expression, and pathological data from AD patients and mouse models to find new therapeutic candidates, which they will test in animal models.

“I think Golde’s approach holds great promise for finding new treatment targets,” Cindy Lemere at Brigham and Women’s Hospital wrote to Alzforum. She is not involved in the work.

“Funding these three projects at the same time will allow for synergy in terms of sharing data, analytical tools and insights and potentially cross-validating each other’s findings,” Petanceska noted. The community at large can also test the proposed models coming out of this research. Since these studies aim to identify biological networks that drive the disease, the findings could spur the rational development of combination therapies for slowing AD progression, Petanceska added. Many scientists believe drug combinations will be necessary to arrest the disease (see ARF related news story; ARF related news story).—Madolyn Bowman Rogers.

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  1. Several of these awards focus on systems biology approaches, using human or animal model tissue, to identify networks and pathways implicated in Alzheimer's disease. Drs Bennett and De Jager have published several papers illustrating the opportunites of data mining in the extensively characterized clinical-pathological cohorts conducted at Rush, for example in identifying genetic pathways, epigenetic marks and proteomic networks that help to explain connections between pathology and cognition. It is novel and ambitious to use networks, and in particular hubs, or major regulatory steps which either are predicted to be druggable or which lie in pathways implicated by the action of known drugs for 'in silico' drug identification. Alzheimer's disease could benefit from fresh approaches such as this to help to identify biological pathways and targets beyond those that have inspired drug discovery related to amyloid and tau.

  2. NIH Director Francis Collins is the hero of the Alzheimer's cause. He is exercising every ounce of discretion to advance the exciting science in Alzheimer's, perhaps the largest unaddressed health need in the world today.

  3. I agree that all the studies described in this new initiative should be supported, despite the negative results of recent anti-amyloid clinical trials that have focused on treating individuals with symptomatic dementia. It is certainly a good idea to treat the earliest stages of the disease, but I worry that it may be difficult to evaluate treatments of asymptomatic individuals using the biomarkers that have been proposed. It is also important to keep in mind that the pathogenesis of the beginning stages of the disease has yet to be studied in a systematic way. Amyloid is a factor, but probably not the only one.

References

News Citations

  1. New Shot in Arm for Alzheimer's Research Announced Today
  2. Early ApoE4 Memory Effects, But Do You Really Want to Know?
  3. NIH Director Announces $100M Prevention Trial of Genentech Antibody
  4. DIAN Trial Picks Gantenerumab, Solanezumab, Maybe BACE Inhibitor
  5. As DIAN’s Scope Widens, Funding Narrows
  6. Solanezumab Selected for Alzheimer’s A4 Prevention Trial
  7. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  8. Immune Cell Receptor Gives Aβ a Toxic Edge
  9. Protective Microglial Gene Variant Promotes Phagocytosis
  10. Scavenger Receptor Regulates Inflammasome Activation, IL-1β
  11. Building a Roadmap for Shared Combination Drug Trials

Webinar Citations

  1. Can Network Analysis Identify Pathological Pathways in Alzheimer’s
  2. Neuroinflammation—A Prelude to Alzheimer's?

Other Citations

  1. ARF related news story

External Citations

  1. 2012 NIH Alzheimer’s Disease Research Summit
  2. National Plan to Address Alzheimer’s Disease

Further Reading