Alzheimer's Disease Research Summit offers research recommendations

The Alzheimer’s Disease Research Summit 2012: Path to Treatment and Prevention, held May 14-15, 2012, brought together leading experts on Alzheimer’s disease and other complex diseases to identify research priorities and strategies needed to accelerate the development of successful therapies. The Summit was attended by an international group of some 500 researchers, clinicians and members of the broader Alzheimer’s community who contributed actively to the Summit process through extensive input and discussion during the course of the meeting. The topics that were discussed included the current understanding of this complex disorder, the need for more basic research into the pathobiology of Alzheimer’s disease, existing models and approaches to drug development, and new ideas to speed development of effective interventions for treatment and prevention.

View a 5-minute video about the Alzheimer's Disease Research Summit featuring NIH officials and grantees.

The recommendations from the Summit, organized by a subgroup of the 57 speakers and panelists and based on the full Summit discussions, will help guide both the public and private sectors toward meeting research goals set forth in the National Plan to Address Alzheimer's Disease, a national strategy announced at the Summit by Health and Human Services Secretary Kathleen Sebelius to accelerate research and improve clinical care and services.

Specifically, the Summit agenda and the initial recommendations presented here outline a blueprint for an integrated, multidisciplinary research agenda. The recommendations focus on a spectrum of basic discovery and translational research activities critical to the development of disease-modifying as well as symptomatic therapies across the disease continuum for the cognitive as well as neuropsychiatric symptoms of Alzheimer’s disease, and they identify the types of infrastructures, resources, and new public private partnerships needed to successfully implement this translational agenda.

Several overarching and transformative concepts were identified by Summit participants as critical to achieving success in Alzheimer’s disease therapy development, and these emerged repeatedly among the themes brought forward by the different workgroups:

• Recognize the heterogeneity and the multifactorial nature of the disease.
• Employ new research paradigms such as systems biology and network pharmacology.
• Enable rapid and extensive sharing of data, disease models, and biological specimens.
• Build new multidisciplinary translational teams and create virtual and real spaces where these teams can operate.
• Develop strategies to overcome intellectual property barriers to Alzheimer’s disease drug development.
• Develop new public-private partnerships.
• Establish a National Institutional Review Board (IRB) for Alzheimer’s disease clinical research.

Specific recommendations are presented here:

Session 1: Interdisciplinary Approach to Discovering and Validating the Next Generation of Therapeutic Targets for Alzheimer’s Disease

1. Intensify scientific efforts to deepen the understanding of the complex pathobiology of Alzheimer’s disease, and diversify target identification to better address the multifactorial nature of the disease. These efforts should include the use of systems biology approaches and tools, as well as cutting-edge stem cell technology.
2. Develop a better systems-level understanding of how the many discoveries that have already been made (e.g., genetic, pathological, biochemical, radiological, neuropsychological) and the contributory factors that have already been identified (e.g., Ab, tau, apoE4, a-synuclein, TDP-43, aging, proteostasis failure, mediators of inflammation, comorbidities) are related mechanistically.
3. Facilitate the conversion of existing genetic information into mechanistic insights and therapeutic advances and continue to generate new genetic data using exome and genomic sequencing approaches to identify rare genetic variants of large functional effect.
4. Generate new experimental models (e.g., different animal species, human induced pluripotent stem [iPS] cells, in silico models) that better simulate the multifactorial etiology of Alzheimer’s disease and use these models to identify modulators of disease pathways and to assess combination treatments which may be required to defeat this disease. Ensure that these new tools and models are freely shared.
5. Develop in vivo imaging agents (tracers for PET scans) to assess target engagement and the burden of brain pathology to enable successful drug development for existing and new therapeutic targets.
6. Develop robust biomarkers that can feasibly be obtained in large cohorts of volunteers, including metabolic signatures to develop and validate diagnostic, prognostic, and surrogate biomarkers for Alzheimer’s disease and biomarkers for disease subtypes.
7. Establish links among peripheral biochemical changes (e.g. blood-based markers) and imaging and cerebrospinal fluid changes to identify and validate peripheral biomarkers of disease.
8. Enable rapid sharing of new data via web-based resources with the capacity to store large and diverse datasets (such as data about clinical phenotypes, genetics, epigenetics, proteomics, and metabolomics) that can be used for testing different models or hypotheses at the computational level.
9. Enable analysis of new data before publication, using approaches such as collaborative challenges open to all citizens and scientists.
10. Maximize the use of existing infrastructure and resources (e.g., research centers, biobanks, and repositories) by publicizing their availability to researchers.
11. Facilitate the creation of new translational teams to expedite the discovery and validation of new therapeutic targets. These teams should include epidemiologists, basic research scientists, geneticists, computational biologists, medicinal chemists, pharmacologists, toxicologists, pharmacogenomics experts, clinicians, and project managers, collaborating within and across institutions.

Session 2: Challenges in Preclinical Therapy Development

1. Develop infrastructure and resources to increase the likelihood that preclinical therapeutic development efforts for Alzheimer’s disease will translate to success in the clinic by:
   • Creating expert advisory committees for all aspects of preclinical and early clinical drug development to assist academic drug discovery efforts
   • Establishing a network of Alzheimer’s disease preclinical therapy centers integrated with existing and proposed translational infrastructure and resources (e.g., Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Centers)
   • Establishing an open-access resource for reviewing and publishing negative and discrepant data.
2. Develop broad capabilities in quantitative and systems pharmacology to understand the impact of drugs on organisms, to predict dosing, to reduce toxicity, and to facilitate drug repurposing and the identification of combination therapies. This will require a wide collaboration among NIH Institutes, government, academia, industry, voluntary health organizations, and foundations including the establishment of new training programs.
3. Increase the predictive power of preclinical testing in animal models by:
   • Establishing a standardized and rigorous process for the development and characterization of animal models, and ensuring their maximal and rapid availability to all researchers for preclinical drug development
   • Aligning the pathophysiological features of Alzheimer’s disease animal models with the corresponding stages of clinical disease using translatable biomarkers
   • Establishing guidelines for rigorous preclinical testing in animal models and reporting of both positive and negative findings.
4. Provide an expedited review track for applications focused on drug discovery, preclinical, and clinical drug development for Alzheimer’s disease to mitigate difficulties with intellectual property and commercialization issues that are imposed by the current lengthy review/grant cycle at the NIH. Establish multi-disciplinary review panels with adequate expertise to evaluate all aspects of translational research.

Session 3: Whom to Treat, When to Treat, and What Outcomes to Measure

1. Initiate treatment trials in asymptomatic, at-risk individuals (e.g., individuals at risk genetically, older adults positive for biomarkers for Alzheimer’s disease) using uniform biomarkers and cognitive outcomes, informed by data from Alzheimer’s disease trials using patients with more advanced disease.
2. Collect DNA and other biosamples from these studies to enable subsequent interrogation based on treatment response and predictors of decline in the groups receiving placebo.
3. Expand large-scale registries and natural history cohorts of healthy individuals from early midlife to late-life, as well as individuals with subjective and/or objective cognitive impairment and use the data generated to inform clinical trial design. These cohorts should be population-based and should oversample underrepresented ethnic minorities and groups with lower education.
4. Develop, validate, and standardize sensitive neuropsychological and other clinical and behavioral measures to detect and track the earliest clinical manifestations of Alzheimer’s disease and to predict long-term clinical and functional outcomes. These measures should be sensitive to change and capture the variability in cognitive function that may be an important predictor of treatment response.
5. Optimize biomarkers for detecting and monitoring the progression of Alzheimer’s disease, and focus particularly on standardization. These biomarkers will be used to elucidate the temporal trajectories over the course of preclinical and prodromal Alzheimer’s disease, to assess the proximity to onset of clinical symptoms, and to predict long-term clinical response to treatment.
6. Develop treatments for patients with symptomatic Alzheimer’s disease and support proof of concept studies to validate novel targets for cognitive and neuropsychiatric symptoms across all disease stages.
7. Develop approaches to stratify and individualize treatments based on the heterogeneity of symptomatic patient populations.
8. Support broad infrastructure changes that will accelerate and improve the efficiency of prevention initiatives, including the formation of a national centralized Institutional Review Board for multi-center Alzheimer’s disease trials and the development of agreements for data sharing of de-identified data from both placebo and treatment arms via public databases.

Session 4: Drug Repurposing and Combination Therapy

1. Expand publicly available libraries of drugs, drug signatures, and Alzheimer’s disease tissues and publicize their availability to the Alzheimer research community. Consider including cell-type and region-specific expression differences in the brain and periphery at varying stages of Alzheimer’s disease, as different stages may require different drugs. Expression libraries from cognitively normal adults positive for amyloid imaging and CSF Alzheimer’s biomarkers and from centenarians without dementia could be used to identify Alzheimer’s disease-resistant expression signatures that correlate with specific drug signatures for prevention studies.
2. Maintain rigor in the development of repurposed drugs with respect to scientific rationale, as well as design of clinical trials. Provide adequate prior clinical trial evidence for safety in populations with or at risk for Alzheimer’s disease.
3. The optimal therapy for Alzheimer’s disease may involve the use of drug combination cocktails and require different composition of these cocktails at different stages of the illness. To facilitate the development of effective combination therapies, develop translational workgroups that include experts in network biology and network pharmacology.
4. Encourage the evaluation of drugs that simultaneously target multiple disease pathways (e.g., insulin, selective estrogen receptor modulators).
5. Develop translational groups across institutions that focus on specific therapy development efforts (e.g., apoE therapeutics, combinatorial therapeutic strategies, drug repurposing, neuropsychiatric symptoms).

Session 5: Nonpharmacological Interventions

1. Integrate epidemiological studies with mechanistic research to explore underlying pathways by which risk and protective factors contribute to the disease process.
2. Continue to identify the molecular mechanisms by which non-pharmacological interventions operate and employ systems biology approaches to examine brain health in relation to, and in concert with, other organ systems.
3. Initiate rigorously designed clinical trials in asymptomatic and cognitively impaired older adults to establish the effectiveness of physical exercise, cognitive training, and the combination of these interventions for Alzheimer’s disease treatment and prevention.
4. Combine nonpharmacological (e.g., behavioral, lifestyle, environmental) interventions with pharmacological treatments to maximize possible therapeutic benefit. Use epidemiologic information, mechanistic research in animal models, and network analysis to inform trial design and drug selection.
5. Develop standard outcome measures to enable data comparisons across studies. These include but are not limited to ecologically valid measures of real world function, quality of life, and physical and cognitive function.
6. Pursue the science of behavioral change for successful implementation of effective nonpharmacological interventions.
7. Invest in research to develop technologies that promote prevention and treatment trials, clinical care, caregiver support, and in-home monitoring.

Session 6: New Models of Public Private Partnerships

1. Promote and enable partnerships across all sectors involved in basic, translational, and clinical research to successfully implement an integrated translational research agenda.
2. Increase awareness of the importance and value of public private partnerships among federal agencies, other stakeholder organizations, and the public and engage the full spectrum of the Alzheimer’s disease community in various partnership activities for the advancement of AD therapy development.
3. Enable partnerships for:'
   • Data sharing (with standardized ontologies and metadata)
   • Creating, validating and sharing tools for translational research (e.g., instruments and biomarkers, animal models, high-throughput screening assays, iPS cells).
   • Expanding the precompetitive space using new models of public private partnerships such as the Arch2POCM partnership for target validation and also for product development partnerships.
4. Develop a National Institutional Review Board for Alzheimer’s disease studies accessible to both public and private funding research organizations.