NATIONAL PLAN TO ADDRESS ALZHEIMER'S DISEASE: 2017 UPDATE. Strategy 1.B: Expand Research Aimed at Preventing and Treating Alzheimer's Disease and Related Dementias

09/01/2017

Investigator-Initiated Research. In 2016, investigator-initiated research offered new insights into the complex molecular, biological and genetic factors that influence disease onset and progression. This work expands our basic understanding of AD/ADRD.

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Collaborating on Drug Targets. Accelerating Medicines Partnership - Alzheimer's Disease (AMP-AD) is part of the Accelerating Medicines Partnership (AMP), a bold venture among the NIH, ten biopharmaceutical companies, and several non-profit organizations aiming to identify and validate the most promising biological targets of disease for new diagnostic and drug development. To date, over 100 novel candidate targets have been identified and are being evaluated in collaboration with industry partners.

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Promising Drugs to Treat or Prevent Alzheimer's Disease. Currently over 50 National Institute on Aging (NIA)-supported clinical trials for AD/ADRD treatment and prevention are underway. In addition, NIH supports about 80 projects aiming to discover and develop new therapeutics for AD/ADRD.

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Identifying Genetic Risk and Prevention Factors. NIH funds cutting-edge research into the genetic underpinnings of AD/ADRD, analyzing how genome sequences -- the order of nucleotides in a cell's DNA -- may contribute to increased risk or protect against the disease. The ultimate goal is to find new pathways for treatments and prevention.

The Alzheimer's Disease Sequencing Project (ADSP) generated three sets of data in the Discovery Phase to determine the order of all 3 billion letters of individual genomes: (1) Whole-genome sequence (WGS) for 584 participants; (2) Whole Exome Sequence (WES) for ~5,000 each of AD cases and controls; and (3) WES of an enriched sample set comprised of over 800 AD cases from multiply affected families and 171 Hispanic controls. In 2016, the ADSP completed the sequencing for the next phase of the project, the Discovery Extension Phase, which has two components: (1) the ADSP Discovery Family-Based Extension Study: To further assess the genomes in multiply affected families; and (2) the ADSP Discovery Case-Control Based Extension Study: To increase the diversity of sample sets. The total number of WGS available for analysis is now well over 4,000. Additional NIA-funded studies that are sharing their data with the ADSP bring that total close to 7,000 whole-genomes.

By 2016, using a combination of genetic analysis approaches, more than two dozen genetic regions of interest had been identified that play a role in AD risk. The specific regions are now being closely examined to determine what genes and cellular pathways are involved.

The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) was established to share genetic/genomic and phenotypic data with the research community. In 2016, they responded to data requests from 60 labs at 43 institutions in order to facilitate the sharing of sequence data with the genetics community. NIAGADS has established several data and information technology resources for the research community at-large, and provides a web user interface that integrates AD/ADRD genetic findings with other genetic data for rapid analysis of the sequence data.

Also in 2016, NIA funded the Genomic Center for Alzheimer's Disease (GCAD). The mission of this Center is to identify genetic variants that cause or influence risk, or protect against AD, and to identify the underlying genes affected by these variants. Its goals are to facilitate AD gene discovery, harmonize all ADSP sequence and genetic and phenotypic data, and to coordinate ADSP data analysis. To date the sequence data for more than 4,000 subjects has been quality control checked and harmonized.

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Genes for Healthy Aging. In 2016, a group of NIH-supported scientists found that genes that promote cognitive health may also help protect against chronic disease of old age, including AD. The "Wellderly" study focused on exceptional individuals from across the United States aged 80-105 who had not developed any chronic medical condition or diseases, including heart disease, cancer, stroke, stroke, AD, Parkinson's disease, or diabetes. In genome-wide association study analyses, two of the top three hits associated with healthy aging were genes previously linked to cognitive function, suggesting that protection against cognitive decline contributes to healthy aging. This is the first large WGS study to focus on health rather than disease. Future studies of this kind will likely reveal additional genes and drug targets that could help protect against AD and other chronic diseases of old age.

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Testing Therapies at Earliest Stages of Alzheimer's Disease. Several NIA-supported clinical trials are testing new paradigms about when the disease starts, and if intervening in symptom-free but at-risk people in the earliest stages of the disease might forestall symptoms and delay progression. In 2014, recruitment began for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, which is testing the drug solanezumab in 1,000 cognitively normal volunteers, age 65-85, who through imaging have been shown to have enough of the amyloid protein in the brain to put them at-risk for developing AD, but do not show clinical symptoms of the disease. This study is still actively recruiting participants. Another trial, the Generation Study, launched in early 2016, will test whether two drugs targeting amyloid, CAD106 and CNP520, can prevent or delay AD/ADRD symptoms in symptom-free older volunteers at high genetic risk for the disease. Recruitment continues for over 1,000 volunteers who carry two copies of the APOE e4 allele, a gene risk factor for Late-Onset Alzheimer's Disease (LOAD).

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A Genetic Connection between Immunity and Alzheimer's. In 2016, a group of researchers supported by the NIH found that Alzheimer's disease shares biological mechanisms with autoimmune diseases. The team used a new genetic approach to analyze data from 17,008 people with AD and 37,154 age-matched controls from four consortia in Europe and North America. The team identified two autoimmune disease-linked genetic alterations that increased AD risk. The first alteration has been linked to psoriasis, while the second has been linked to both Crohn's disease and inflammatory bowel disease (IBD). The genetic variation linked to Crohn's and IBD correlated with a 50% faster rate of cognitive decline in people with AD, mild cognitive impairment (MCI), and in healthy controls. This discovery adds to the mounting evidence that the immune system plays a key role in the development of AD.

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Lifestyle Alzheimer's Disease Prevention. NIH is studying whether lifestyle interventions, such as diet, exercise, and cognitive enrichment, may be preventive interventions for cognitive decline and AD. Currently, a number of NIH-funded clinical trials are underway to test whether exercise can influence AD onset and progression. For example, one active study is currently recruiting participants and using brain imaging and cognitive measures to investigate the effects of cycling on cognition and hippocampal volume.

NIA has recently funded the Exercise in Adults with Mild Memory Problems (EXERT) trial to test whether moderate/high aerobic exercise and stretching can slow the progression of MCI to AD in adults over 65. This 18-month long trial is actively recruiting participants.

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Discovering the Molecular, Cellular, and Genetic Causes of Alzheimer's Disease and Related Dementias. NIH funds a broad range of research to understand the underlying causes of dementia, which is an important first step for developing new treatments and prevention strategies. To better understand the vascular contributions to AD/ADRD, NIH launched the Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease Consortium (M2OVE-AD) in March 2016. The 5-year, $30 million program brings together over a dozen research teams working on five complementary projects. Scientists from diverse fields using the latest methodologies will work collaboratively towards shared goals: to dissect the complex molecular mechanisms by which vascular risk factors influence AD/ADRD and identify new targets for treatment and prevention.

In the fall of 2016, NIH added a new team to the M2OVE-AD Consortium to zero in on the how sex differences impact the trajectory of the disease; with the largest current study of gene expression mechanisms in postmortem human brains in AD. It is hoped that this closer look at the sex differences in disease progression can provide major insights related to the overall understanding of AD biology, and help direct us toward new drugs targeted specifically for women or men at-risk for dementia.

Recently, NIH-funded scientists have found links between cerebrovascular diseases, cognition, and brain aging by using data from large population studies, and are exploring new targets and strategies to reduce FTD-related pathologies. In addition, researchers identified a role of tau pathology in LBD, and are developing animal models to study genetic causes of LBD.

In addition to continuing support for investigator-initiated research, in 2016, NIH released requests for applications (RFAs) to stimulate research on how to better study and diagnose small vessel disease in the brain as it relates to cognitive decline and dementia, and created a new cross-disciplinary program to investigate the molecular mechanisms of tau toxicity in FTD. In 2017, NIH released a new ADRD funding opportunity to create the FTD Sequencing Consortium that would support WGS and replication studies to find and validate new risk genes for FTD.

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Bridging the Preclinical to Clinical Development Gap. In 2017, NIH launched the Model Organism Development and Evaluation for Late-onset AD, an initiative that will create the next generation of mouse models to be used in preclinical efficacy testing of candidate therapeutics. The new models will be based on newly identified LOAD risk genes and will undergo extensive molecular, pathological and clinical staging to align the pathologic features in mice with corresponding stages of human disease.

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Addressing Health Disparities. Race and ethnicity, and socioeconomic status can influence AD/ADRD risk and outcomes. To identify and better understand biological, behavioral, sociocultural and environmental factors that influence health differences, NIH is supporting several new research efforts: some researchers will focus on improved recruitment and cognition assessment tools for health disparities, while others examine disparities in access to and use of LTSS, which includes institutional care and HCBS, for persons with dementia. A primary goal is to develop treatment and prevention strategies that are effective and culturally appropriate among diverse populations.

One recent study, for example, looked at possible genetic influences that might explain differences in AD prevalence among African Americans and non-Hispanic Whites. Researchers found an increased genetic risk for AD in African Americans due to variations in a gene for the brain's system for clearing out beta-amyloid protein fragments. The team confirmed that this deletion mutation was associated with increased AD risk in two large African American populations, but found the mutation virtually absent in samples from over 3,000 non-Hispanic Whites.

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NIA Enhances Information on Alzheimer's Clinical Trials Participation. NIA continues to promote participation in AD/ADRD clinical trials, studies, and registries through our Alzheimer's Disease Education and Referral (ADEAR) website portal; clinical trials listing and monthly e-alert to more than 35,000 subscribers; social media messages through Facebook and Twitter; promotion of the Recruiting Older Adults into Research (ROAR) toolkit of customizable materials for aging services and public health professionals to use in community settings and social media in English, Spanish, and Chinese, and collaboration with the Administration for Community Living (ACL), Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA) and the Patient-Centered Outcomes Research Institute (PCORI)-funded Alzheimer's and Dementia Patient/Caregiver-Powered Research Network to encourage research participation among older adults.

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Developing a National Recruitment Strategy. With substantial community and stakeholder involvement, NIA is leading efforts to provide practical approaches to help study sites and researchers overcome the challenges and barriers in recruiting and retaining the right volunteers, at the right times, in the right studies. In facilitation with the Alzheimer's Association and collaboration with government, private, and academic stakeholders, NIA is developing the National Strategy for Recruitment and Participation in Alzheimer's Disease Clinical Research. In 2017, NIA convened a workshop for experts from academia, communications, advocacy, and clinical care and research to identify the best strategies for engaging a range of audiences, including minority and underrepresented groups, in the clinical research enterprise.

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VA Targets Dementia Research. The U.S. Department of Veterans Affairs (VA) Office of Research and Development (ORD) has ongoing specialty AD RFAs for biomedical laboratory or clinical research to include FTD, LBD, and/or VCID in addition to AD/ADRD.

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VA Collaborates with NIA. VA/ORD and NIA have initiated the Strategic Partnership to Advance Research and Knowledge, which is a joint VA-NIA cooperative partnership of shared dementia research priorities with the goal to develop and implement a sustainable framework to facilitate supportive resources and co-funding.

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Frontotemporal Degeneration Disorders Registry. The FTD Disorders Registry LLC (FTDDR) is an independent non-profit entity co-founded by the Association for Frontotemporal Degeneration (AFTD) and the Bluefield Project for the Cure. The shared vision for a patient registry to serve the frontotemporal disorders community was realized with the formal design, build, and beta testing of the web interface occurring throughout 2016. The FTDDR is a Contact and Research Registry, where research recruitment is initially focused in the United States and Canada, while Contract Registry enrollment is international. The Registry welcomes persons diagnosed with FTD, their caregivers, family and friends to join. Research participation is primarily comprised of data collection via online surveys; de-identified data will be cultivated, aggregated and analyzed. This dynamic online database will function as the central resource for the lay community and the research/development community with overriding objectives to support research, clinical trial recruitment, and drug development. Spring 2017 marks the formal FTDDR public launch.

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Treat Frontotemporal Degeneration. In May 2016, the Alzheimer's Drug Discovery Foundation (ADDF) and AFTD launched the Treat FTD Fund to support clinical trials testing novel or repurposed drugs for FTD and related disorders (bvFTD, PPA, PSP, CBD, FTD/ALS). The Treat FTD Fund will build on recent successes of both foundations in early-stage drug discovery and biomarker development, and leverages new ongoing efforts under development by AFTD such as the recently launched FTDDR and a $5 million FTD Biomarker Initiative. Running clinical trials in FTD patients will help investigators learn how best to target this unique patient population and will employ advances in biomarkers as they develop. Through this partnership, ADDF and AFTD propose to invest $10 million over 10 years to fund at least five innovative clinical trials subject to review by an appointed Joint Steering Committee.

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Lewy Body Dementia Patient Engagement. The Lewy Body Dementia Association (LBDA) launched a new initiative to help drive participation in clinical research studies. This multi-pronged initiative included a webinar about participating in clinical trials, a new section on LBDA's website about new studies and clinical trials, and social media and email campaigns.

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Patient-Powered and Caregiver-Powered Research. UsAgainstAlzheimer's has partnered with the Mayo Clinic, University of California, San Francisco, and University of Florida in the Alzheimer's Disease Patient and Caregiver-Powered Network (AD-PCPRN), funded by PCORI. The project's goal is to accelerate development of effective treatments of AD/ADRD. It is intended to connect patients, caregivers and researchers focused on developing, conducting and disseminating patient-centered dementia research. Through the GALAXY platform developed with UsAgainstAlzheimer's, the AD-PCPRN provides potential clinical trial participants a brief assessment aid powered by Roobrik to map a course of action and a trial matching service, powered by Antidote. The AD-PCPRN is governed by a Governance Council of leaders in AD, advocacy, caregiving and other areas. Providing insights to the Governance Council are four Advisory Councils, whose nearly 45 members include leaders in the AD patient/caregiver community, communications and outreach, diversity outreach and research, and registries/clinical trials.

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Screening for Dementia in Persons with Intellectual and Developmental Disabilities (IDD). The National Institute on Disabilities, Independent Living, and Rehabilitation Research (NIDILRR) is funding a study, led by Dr. Peter Blanck of Syracuse University that is examining cognitive status of older African Americans with IDD with a goal of learning more about the impact of dementia on long-term outcomes and quality of life. In addition, Dr. Matt Janicki and his colleagues at the University of Illinois, Chicago's NIDILRR funded Research and Training Center on Aging with Developmental Disabilities, have produced a rich body of knowledge about cognitive decline and dementia in persons with IDD. Their work includes a useful instrument for detecting early-onset and presence of dementia in persons with IDD.

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