01 Jun 2018

The third summit on AD since 2012, called NIH Alzheimer's Research Summit 2018: Path to Treatment and Prevention, was scheduled for March 1 and 2 at the institute's Bethesda campus in Maryland. Day one went off without a hitch (Mar 2018 conference news), but an overnight winter storm that closed the NIH campus left organizers scrambling to reschedule the second day. On May 24, with only panelists revisiting Bethesda, and all others attending by remote video link, the mission was complete. Over the two days more than 80 scientists had presented their and vision and weighed in on research priorities. With this, the NIH compiled a list of research recommendations centered on seven themes but organized under seven different headings. Confused? The nearly 100 published recommendations and sub-recommendations are grouped by the summit’s seven session titles:

• Novel Mechanistic Insights into the Complex Biology and Heterogeneity of AD
• Enabling Precision Medicine for AD
• Translational Tools and Infrastructure for Predictive Drug Development
• Emerging Therapeutics
• Understanding the Impact of the Environment to Advance Disease Prevention
• Advances in Disease Monitoring, Assessment, and Care
• Building an Open Science Research Ecosystem to Accelerate AD Therapy Development

Yet they fall broadly into these seven themes:

• Developing a better understanding of the complex and multifactorial causes of disease
• Enabling precision medicine research needed to develop interventions that can address the underlying disease process, as well as the disease symptoms, and be tailored to a person’s unique disease risk profile for Alzheimer’s disease
• Enhancing the research infrastructure and developing translational tools to accelerate therapy development
• Supporting the development of novel therapeutics that target the many facets of Alzheimer’s disease
• Understanding the impact of the environment and its interaction with genetic and biological factors to advance effective prevention strategies for Alzheimer’s disease
• Leveraging emerging digital technologies and big data approaches to improve our ability to discover early markers of disease, better track responsiveness to treatment, and provide better care
• Bringing together multiple stakeholders to build a new research ecosystem based on the principles of open science

The National Advisory Council on Aging adopted the new recommendations on May 23 and will use them to update milestones for the National Plan to Address Alzheimer’s Disease, which guides the nation’s research community toward finding ways to treat and prevent dementia by 2025.

Summit Day Two—Take Two
Day two picked up where day one had left off, discussing emerging therapeutic approaches. Researchers briefly reviewed non-amyloid-based therapies in early stage trials. Roberta Diaz Brinton, University of Arizona, Tucson, said her concept of regenerating the flailing brain was gaining traction, with allopregnanolone having just passed toxicology testing and now slated for a Phase 2 trial using a delayed-start, adaptive design. Allopregnanolone has pleiotropic effects, boosting neuro-, oligodendro-, and synaptogenesis, as well as mitochondrial respiration. Along similar lines, Mark Gurney, Tetra Discovery Partners, Grand Rapids, Michigan, announced a Phase 2 trial for the phosphodiesterase 4 inhibitor BPN14770. This drug boosts the CREB pathway, which is essential for early and late memory, and reportedly stabilizes synapses by ramping up production of brain-derived growth factor (BDNF; see Dec 2017 conference news). Mark Tuszynski, University of California, San Diego, also plans to boost BDNF, but by delivering the gene directly into the brain. Tuszynski pioneered this strategy using nerve growth factor, but that did not pan out as a viable treatment (Mar 2018 news). Targeting the gene to the right place in the brain was problematic, he said. For BDNF, he plans to use MRI imaging to guide placement of the engineered vector into the brain. Complementing these regenerative strategies, Frank Longo, Stanford University, Palo Alto, California, has developed a small molecule modulator of the neurotrophin p75 receptor. LM11A-31 counteracts degenerative signaling in the AD brain, appeared safe in a Phase 1 trial, and is now being tested in Phase 2A in Europe, Longo said in Bethesda.

Linda Van Eldik, University of Kentucky, Lexington, and Martin Watterson, Neurokine Therapeutics, Philadelphia, have collaborated for many years on developing drugs to tamp down inflammation in the brain. In Bethesda, Van Eldik reviewed MW151, a compound that came out of a functional screening program and blocks biosynthesis of cytokines. Van Eldik said MW151 is the first in its class, has good safety and metabolic profiles in preclinical testing, and she expects to file an Investigational New Drug application for it soon. Given orally at low doses, MW151 suppresses cytokine overproduction in mice, including two models of AD, but Van Eldik did not elaborate on how it works. Meanwhile, MW189, an intravenous formulation of MW151 that is being developed for acute conditions such as a traumatic brain injury or intracerebral hemorrhage, is finishing a Phase 1 study in healthy adults. Van Eldik told Alzforum she is seeking sponsorship to begin Phase 2 (May 2017 conference news). In giving an update on a third compound, MW150, Watterson said being a p38α kinase inhibitor it also suppresses cytokine production but by a different mechanism of action to MW151/189. He said preclinical toxicology raised no safety issues, and the compound is now being tested in Europe in people for the first time.

Michela Gallagher and colleagues at Johns Hopkins University, Baltimore, have adopted a different therapeutic strategy. They are trying to temper hyperactive neural circuits. Gallagher reviewed levetiracetam, an anticonvulsive medication being repurposed for use at low doses in dementia. It has been poised for Phase 3 testing for some time (Dec 2016 conference news). Then Gallagher introduced GABA-A α5-positive allosteric modulators, a new class of potential therapeutics for AD. Gallagher said that GABA-A α5 receptors are highly enriched on the same neurons that are overactive in prodromal AD, and that activating them boosts tonic inhibition of those same neurons. The NIH Blueprint Neurotherapeutics Network supports lead optimization in that program, Gallagher told Alzforum.

In another stab at repurposing, Alice Taubes, University of California, San Francisco, outlined how she screens for previously approved drugs that can reset AD-type transcriptomic profiles back to something that looks more normal. “In the age of big data, we can allow the brain to tell us what it needs, rather than trying to figure it out from the literature,” Taubes claimed. She integrates transcriptome profiles from large data sets, such as AMP-AD, to find consensus disease signatures, then looks for drugs that can normalize up- or downregulated genes. She has screened 13,000 compounds and is studying the top hit to find out how it works. Similarly, Rong Xu, a computer scientist from Case Western Reserve University, Cleveland, laid out how computational analysis followed by experimental testing might identify approved drugs that could benefit AD patients. Her goal is to review known drug side effects that indicate altered brain function, then test those drugs in mouse models to determine their mode of action.

In the remaining sessions, researchers focused on the importance of understanding environmental exposures in advancing disease prevention; advances in disease monitoring, assessment, and care; and how to build an open science research ecosystem to accelerate therapeutic development. As on day one, big data and advanced technologies were a common theme. For example, Kelly Bakulski, University of Michigan, Ann Arbor, stressed how little is known about the role of pollutants. She said the U.S. produces more than 85,000 different types of chemicals, of which only 300 have undergone rigorous health and safety testing by the Environmental Protection Agency, and only five have been banned outright. “We are vastly underinformed about the health consequences of chemicals in our everyday environment,” she said. Bakulski said that studying the “exposome” will be an important advance.

Xu stressed that big data and computational approaches can be brought to bear to understand how environmental exposure and genetics combine to affect dementia risk. With 85,000 chemicals and 30,000 genes, the permutations are almost incalculable, she said. Xu uses computational algorithms to crunch numbers from large data sets in search of clues to how chemicals affect brain function. She started with 171 metabolites from gut bacteria, combining chemical genetics and GWAS databases to predict how they might associate with diseases, including AD. Andrew Saykin, Indiana University, Indianapolis, emphasized the microbiome as well, noting that there are more microbes in a person’s gut than human cells in his or her body. Data from the ADNI and ROSMAP studies suggest correlations between secondary bile acids generated by the microbiome and cortical thickness, glucose metabolism, and longitudinal cognitive decline, Saykin said.

Looking at the bigger societal picture, Jennifer Manly from Columbia University, New York, noted how dementia incidence and risk factors can be dictated by race, ethnicity, and social demographics, which are all affected by the environment. Laura Baker, Wake Forest School of Medicine, Winston-Salem, North Carolina, reviewed the rationale behind POINTER, the U.S. multidomain intervention trial based on the FINGER trial in Europe (Aug 2017 conference news). Hiroko Dodge, Oregon Health & Science University, Portland, studies web-based tools that enhance social engagement. She described I-CONECT, a.k.a. the Internet-based Conversational Engagement Clinical Trial. It will test if 30-minute video chats two to four times a week over a year benefit cognition among socially isolated people aged 80 and older.

On the use of technology for monitoring, data collection, and intervention, Jeff Kaye, Oregon Health & Science University, Portland, reviewed the CART initiative, which stands for Collaborative Aging (in Place) Research Using Technology. This is a collaborative effort among academics, industry, and the NIH to develop tools for home monitoring. Kaye noted the challenges in setting up a system that relies on many moving parts, including computers, wearable sensors, home Wi-Fi devices, specialized software, all integrated with electronic health information and analysis. Nevertheless, he said, prototypes have been deployed to homes at four different sites around the U.S: Portland, Oregon; Northwest Virginia; Chicago; and Miami.

Mariana Figueiro from Rensselaer Polytechnic Institute, Troy, New York, outlined how one technological advance—tailored lighting—can improve circadian rhythm, sleep patterns, behavior, and mood in AD patients. Andrew Lim, University of Toronto, urged that wearable technologies and better animal models be used to study disturbances of sleep and circadian rhythm in dementia, while Daniela Brunner, founder and CEO of Early Signal, a nonprofit that develops smart technology to capture data from wearable devices, noted that device reliability, data collection and storage, and consent all still pose problems. On the latter, Dorothy Farrar-Edwards, University of Wisconsin, Madison, said that e-consent, which simplifies the often mind-boggling, booklet-sized consent forms, has enrolled almost 60,000 people and could be a useful tool for AD researchers. Ardy Arianpour, CEO and founder of Seqster, said his goal was to provide a means for people to own their own health data. People should be able to not only store the data in one place that’s accessible to researchers, but also to will it so that when they pass on the information is there for posterity.

In the last session, panelists led by Eric Reiman, Banner Alzheimer’s Institute, Phoenix, discussed how to build an open system that will accelerate research. Noting the success of ADNI, API, AMP-AD and other collaborative projects with commitments to open data sharing, Reiman stressed that going forward, it will be essential that scientists share data and samples from clinical trials and academic studies. It will be critical to do this in a productive and cordial way that values sharers, Reiman said. As an example, Lara Mangravite, from the nonprofit Sage Bionetworks, Seattle, noted that AMP-AD now shares 60,000 files from 42 investigators across 22 institutions with samples from 36 research studies. Suzana Petanceska, NIA, said that when the concept AMP-AD was first floated, some said this degree of sharing was a terrible idea for young investigators, who would be scooped. That has not happened. “I feel we often use young investigators as a human shield against data sharing,” said Petanceska. “I’m happy to say they are doing fine and several already have their own labs. It’s the rest of us who need to change.”—Tom Fagan

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References

News Citations

1. Big Data Was the Big Theme at Shortened NIH Summit 10 Mar 2018
2. In the Running: Trial Results from CTAD Conference 14 Dec 2017
3. NGF Gene Therapy Trial Data Published 29 Mar 2018
4. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration 11 May 2017
5. Emerging Alzheimer’s Therapies Test the Waters at CTAD 30 Dec 2016
6. New Dementia Trials to Test Lifestyle Interventions 11 Aug 2017

Therapeutics Citations

1. Allopregnanolone
2. AGB101

External Citations

1. recommendations and sub-recommendations
2. Phase 2A
3. NIH Blueprint Neurotherapeutics Network
4. Conversational Engagement Clinical Trial

Further Reading

No Available Further Reading