On February 9 and 10, leaders from academia, industry, and non-profit organizations gathered at the Natcher Auditorium of the National Institutes of Health (NIH) in Bethesda, Maryland, for the Alzheimer’s Disease Research Summit 2015. They discussed the progress made since the last such meeting in 2012 (see May 2012 conference series) and outlined new recommendations going forward. The first day’s sessions were on current and future clinical trials, finding new drug targets, and seeking methods of prevention. The second day covered ongoing projects to share data more widely, ways to engage participants in research, and how to involve citizen scientists in helping analyze large datasets (see Part 2 of this series). Overall, the meeting served to refresh the field’s plan to prevent and better treat Alzheimer’s disease by 2025.

Natcher Building at the National Institutes of Health.

“This was an attempt on the part of the NIA to step back, take a survey of the field, and try to figure out what has been working, what hasn’t been working, and what new things should we be trying,” said David Bennett, Rush University Medical Center, Chicago.

“The field has begun to come together in ways that it never has before, in identifying an overall strategy for the field,” George Vradenburg of UsAgainstAlzheimer’s in Chevy Chase, Maryland, commented after the meeting. “There’s a sense of urgency associated with the 2025—it’s finally taking hold in a real way.”

NIH director Francis Collins set the tone when he said in his opening remarks, “Our charge for this meeting is to rededicate ourselves to this critically important work and to identify the highest priorities for biomedical research on Alzheimer’s disease and related conditions.” Richard Hodes, who directs the National Institute on Aging (NIA) in Bethesda, added that the recommendations from the meeting would serve to update the National Plan to Address Alzheimer’s disease.

Altering the Scope of Clinical Trials
A key area of progress in the field is that four secondary prevention trials of Aβ monotherapies are underway and several more are in the planning stages (see Dec 2014 news). However, at the summit Reisa Sperling of Harvard Medical School, who is directing one of those trials, urged researchers to start planning the next set of therapeutic trials. She advocated treating even earlier in disease, and evaluating combinations of investigational drugs. FDA official Rusty Katz forcefully recommends combination trials as well (see Nov 2014 conference news). Reminding the audience of Katz’s recent speech, Sperling pointed out that the current prevention trials will take years to read out, and argued that the field cannot wait to see if they work before taking the next step. She advised combining an Aβ therapy with a tau therapy, given that tau pathology leads to faster memory decline in the presence of Aβ buildup (see Feb 2015 conference news). Since such trials may require cooperation between companies, she suggested building resources that encourage pharmaceutical cooperation, such as trial-ready cohorts of participants and easier communication with regulatory authorities.

Julie Stone, from Merck in West Point Pennsylvania, cautioned that combination trials are highly complex, given that researchers still struggle to interpret trials with one drug candidate. Stone uses quantitative systems pharmacology. This discipline integrates experimental data from different sources to model complex biological systems and help design late-stage trials. This approach lets her map out an underlying disease process, figure out what doses of drugs might perturb it, and predict outcomes of trials. Stone explained how Merck has partnered with academic researchers to build a model of the amyloid pathway, with secretases and biomarkers, and empirical results from multiple Phase 1 studies of Merck’s BACE inhibitor. This model used data on the degree of Aβ reduction achieved in smaller studies and helped the company choose the doses of MK-8931 now used in the Phase 3 program. Given that the researchers now know more about the drug’s effects on amyloid, the resulting trial should be a solid test of the amyloid hypothesis, Stone said. She encouraged experimental scientists to partner with systems pharmacologists to help build similar models. They help scientists revisit data from previous failed trials and figure out whether they actually tested their underlying hypothesis, she said.

Careful analysis of failed trials would accelerate the field’s efforts toward its 2025 goal, agreed Samantha Budd Haeberlein from Biogen Idec in Cambridge, Massachusetts. Since papers on negative trials are rarely published, at least not with full data, some of the reasons for failure are doomed to be repeated. Rather, these analyses could be encouraged and openly shared, Budd proposed.

Hunting for Effective Targets
Even as trials are underway for Aβ therapies, and drugs aimed at tau are entering early stage trials, researchers are actively searching for new targets for Alzheimer’s disease. At the summit, David Bennett of Rush University, Chicago, reviewed the complexity of the protein pathologies underlying age-related dementing disorders. In his view, even if Aβ and tau treatments prove successful, they might treat only half of all people with AD dementia, Bennett said.

Speakers at the summit recommended going after a wide range of candidates. One prime suspect is the immune system, which research indicates is highly involved in AD but has been elusive in terms of yielding druggable new targets. Philip de Jager, Brigham and Women’s Hospital, Boston, described some of his recent work, including his finding that monocytes are more important in AD than T cells (see May 2014 news). De Jager proposed studying communication between the peripheral and central immune systems and how this could render someone susceptible to AD. He also suggested gaining a better understanding of how the immune system ages, and how that could contribute to the disease.

Vascular changes themselves could make an interesting target, said Berislav Zlokovic, University of Southern California, Los Angeles. His recent studies suggest that in aging, the blood-brain barrier starts to break down in the hippocampus, more so in people with mild cognitive impairment (see related Webinar). He proposed testing whether such vascular changes precede Alzheimer’s, if AD genes affect vascular function, and if treating dysfunction influences neurological disorders. 

What about the synapse? As the functional unit of the nervous system vulnerable to both Aβ and tau, the synapse could hold new insights into the biology of AD. Several speakers at the summit, particularly Li-Huei Tsai of MIT and Bradley Hyman of Harvard University, advocated using modern techniques such as optogenetics to gain a deeper understanding of synaptic biology in aging and neurodegenerative diseases, and urged neurochemists to get involved in developing PET ligands that image synaptic function in patients to track the disease.

Gerard Schellenberg, University of Pennsylvania, Philadelphia, argued that new therapeutic targets could be found by ramping up genetics research to unravel the full genetic burden of Alzheimer’s disease. Sometimes rare functional variants prove to be good starting points for therapy development. Schellenberg cited a recent success in heart disease, where a cholesterol-clearing, loss-of-function mutation in the PCSK9 gene was first reported to be protective in 2006 (see Cohen et al., 2006). This inspired the development of therapeutic antibodies to the affected protein, which have proven safe and effective in Phase 2 and 3 trials (see Rodriguez and Knowles, 2015). For AD, Schellenberg proposed boosting sample sizes in genetics studies by sharing data, while using more high-throughput biology methods to translate findings into therapeutic targets.

Alison Goate, Mt. Sinai Hospital, New York, suggested the time was right to focus on finding protective variants against AD. In particular, she recommended looking at people who carry two copies of the ApoE4 allele but have maintained normal cognition into old age, or who have an autosomal-dominant mutation but stay cognitively healthy past their family’s mean age of onset. Both these types of person are rare, but some are known to science and willing to participate in research.

Moving beyond the genome, Jonathan Mill, King’s College London, noted that epigenetic changes are reversible and could make therapeutic targets. He reviewed work on methylation differences in ANK1, a gene involved in cell mobility and structure, in the cortices of people with AD (see Aug 2014 news). This gene also emerges as a hit from GWAS of Type 2 diabetes. Since it is unclear whether epigenetic changes are a cause or a result of neurodegeneration, Mill recommended conducting longitudinal studies to assess when they occur relative to better-known brain markers of AD. He also suggested developing methods to sample purified cell cultures from the brain to look at epigenetic changes with higher resolution.

Claes Wahlestedt, University of Miami, pointed out that hundreds of enzymes modify chromatin in a redundant way, and drugs can therefore target some of those enzymes without wide-ranging side effects. As examples, he mentioned BET bromodomain inhibitors, which are entering clinical trials for cancer. Compared to HDAC inhibitors, these drugs affect far fewer genes in the brain, Wahlestedt said. Similar therapies could hit epigenetic targets that simultaneously affect a number of factors relevant to AD.

Clues to Prevention
While many scientists are looking into potential treatment targets for AD, others are vetting factors that could prevent it. Kenneth Langa, University of Michigan, Ann Arbor, said that global trends in AD hint that better education and control of cardiovascular risk factors are lowering incidence in some high-income countries. This decline is a public health success that could moderate the steep growth in AD cases otherwise expected in the coming decades as a consequence of rising obesity and diabetes in aging populations (see Jul 2014 news). Langa suggested performing more research on these potential preventative pathways. Martin Prince, Kings College, London, followed with data on global dementia trends that suggest low education in early life, as well as hypertension, diabetes, and smoking in mid- to later life, all contribute to the risk for AD. He advocated that countries launch public health campaigns that actively promote the idea of AD as a preventable condition. Above all, more countries should closely monitor rates of dementia over time and see how they correlate with other risk factors, Prince said.

Some scientists would like to systematically probe environmental factors that could alter risk for AD. Chirag Patel, Harvard Medical School, introduced the concept of the exposome, the sum total of a person’s exposures during their lifetime. Patel proposed conducting environment-wide association studies for AD, cataloging chemicals, pesticides, vitamins, drugs, metal, etc., to see how such factors modify a person’s risk for AD. Several technologies could help give an unbiased look at possible exposures, such as methods that measure analytes in serum and urine, he added. Patel recommended building a database to store publicly available longitudinal data on environmental exposures (see Patel and Ioannidis, 2014). Using similar biochemical tools, Rima Kaddurah-Daouk, Duke University, Durham, North Carolina, is working with scientists in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) consortium to characterize changes in the metabolome over the course of AD. By adding a metabolomics layer to the genomic, neuropsychological, and imaging data already collected, researchers may find new biomarkers and therapeutic targets relevant for Alzheimer’s, she said.

A good night’s slumber might also protect against AD, according to David Holtzman of Washington University in St. Louis. During sleep, the brain generates fewer and clears more Aβ monomers (see May 2014 news). Holtzman advised the NIH to encourage more research on how sleep affects underlying Alzheimer’s pathology, and suggested it could lead to better diagnosis and treatment. Holtzman also made the argument that while more money is going toward Alzheimer’s research, it has not funded enough additional R01 grants. He strongly recommended that the NIH boost the percentiles of funded R01s to support more basic and translational science that could address priorities articulated at the summit. His comment garnered a round of applause.

With a number of proposed targets presented on day one, Howard Fillit, Alzheimer’s Drug Discovery Foundation in New York City, wondered how to prioritize them given that the field has limited resources with which to develop a therapy by 2025. Bennett responded that choosing the best candidates will depend in part on data being shared among scientists, who should rigorously try to replicate each other’s work and run extensive computational models before preclinical or clinical testing.

Some scientists remarked privately to Alzforum that they had hoped the meeting would include more cutting-edge science. Others were disappointed that most speakers had pitched their own area, rather than seeking a broader consensus on the most promising ones to take forward.

Click here to view the webcast for day 1.—Gwyneth Dickey Zakaib


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Conference Coverage Series Citations

  1. Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention

News Citations

  1. From Shared CAP, Secondary Prevention Trials Are Off and Running
  2. Rusty Unleashed: Forget Disease Modification, Go for Big Effect
  3. Tau Tracer T807/AV1451 Tracks Neurodegenerative Progression
  4. Alzheimer's GWAS Hits Reflected in Monocyte Gene Expression
  5. Alzheimer’s Brains Mottled with Epigenetic Changes
  6. Falling Dementia Rates in U.S., Europe Hint at Prevention Benefit
  7. Glymphatic Flow, Sleep, microRNA Are Frontiers in Alzheimer’s Research

Webinar Citations

  1. Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?

Paper Citations

  1. . Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264-72. PubMed.
  2. . PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics. Curr Atheroscler Rep. 2015 Mar;17(3):487. PubMed.
  3. . Placing epidemiological results in the context of multiplicity and typical correlations of exposures. J Epidemiol Community Health. 2014 Nov;68(11):1096-100. Epub 2014 Jun 12 PubMed.

Other Citations

  1. Part 2

External Citations

  1. here

Further Reading


  1. . Oral nimodipine reduces prostaglandin and thromboxane production by arteries chronically exposed to a periarterial haematoma and the antifibrinolytic agent tranexamic acid. J Neurol Neurosurg Psychiatry. 1987 Jun;50(6):727-31. PubMed.