National Plan to Address Alzheimer's Disease: 2016 Update. Strategy 1.B: Expand Research Aimed at Preventing and Treating Alzheimer's Disease

08/01/2016

Expanding Basic Understanding of Alzheimer's Disease. Investigator-initiated research reported in 2015 offered new insights into the complex molecular, biological and genetic factors that influence disease onset and progression.

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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. In early 2015, the AMP-AD Target Discovery and Preclinical Validation Project launched a data portal with innovative analytical tools to the wider research community to shorten the time between the discovery of potential drug targets and the development of new drugs.

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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 Discovery phase of the Alzheimer's Disease Sequencing Project (ADSP) determined the order of all 3 billion letters in the individual genomes of 580 participants. It also generated whole exome sequencing data (focused on the proteins influencing the disorder) of an additional 11,000 volunteers -- 6,000 with Alzheimer's compared to 5,000 controls. In 2015, investigators began to identify variations in the genomes of families where three or more family members are affected by the disease. The specific regions are now being closely examined to determine what genes are involved. The ADSP also initiated the Discovery Extension Phase of the study with whole genome sequencing on over 430 more family members.

Two NIH-funded entities are collaborating on managing and making available to the genetics research community the massive amounts of ADSP data: the Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and the Database for Genotypes and Phenotypes. In 2015, NIAGADS released genotypic data generated on more than 11,500 subjects and responded to data requests from 30 labs at 26 institutions in order to facilitate the sharing of sequence data with the genetics community. NIAGADS 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.

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Promising Drugs to Treat or Prevent Alzheimer's Disease. Currently 38 National Institute on Aging (NIA)-supported clinical trials for AD/ADRD treatment and prevention are underway. In addition, NIH supports over 70 projects aiming to discover and develop new therapeutics for AD/ADRD.

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Identifying Ways to Keep Neurons Healthy. As animals, including humans, age or develop brain diseases such as Alzheimer's, their brain cells may not produce enough energy to remain fully functional. Scientists using a new mouse model discovered that an enzyme, SIRT3, may protect brain cells against stresses believed to contribute to energy loss. They also found that physical exercise increases the expression of SIRT3 -- found in mitochondria, the cells powerhouse -- which helped to protect the brain against degeneration in the mice. The findings suggest that bolstering mitochondrial function and stress resistance by increasing SIRT3 levels may offer a promising therapeutic target for protecting against age-related cognitive decline and brain diseases such as Alzheimer's.

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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 (A4) trial, 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. 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 is underway for over 1,000 volunteers who carry two copies of the APOE e4 allele, a gene risk factor for late-onset Alzheimer's.

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Alzheimer's Pathology in the Oldest-Old. The brains of people who live to age 90 and older -- the oldest-old -- usually have a mix of pathologies associated with dementia. AD/ADRD-related brain changes are the most common, but other pathologies often found at autopsy include infarcts, Lewy bodies, hippocampal sclerosis, and white-matter disease. For the first time, NIH-funded researchers examined the relationship between the number of pathologies found at autopsy and the severity of dementia in the oldest-old. They found the more pathologies present in the brain, the more severe the dementia, and that Alzheimer's pathology alone was less damaging to cognition than mixed pathologies. These findings point to the need to target multiple pathologies to reduce the burden of dementia.

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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/ADRD. Currently, five NIH-funded clinical trials are underway to test whether exercise can influence Alzheimer's 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.

Being obese or overweight in middle age has been linked to increased risk of dementia. NIH staff scientists discovered that being obese or overweight at midlife -- as measured by body mass index (BMI) at age 50 -- may also predict earlier age of onset of Alzheimer's. The investigators found that in study participants who developed Alzheimer's, each unit increase in BMI at age 50 accelerated onset by nearly 7 months, that a higher midlife BMI was associated with greater levels of neurofibrillary tangles and amyloid -- hallmarks of the disease -- in the brain. The findings suggest that maintaining a healthy BMI at midlife might be considered as one way to delay the onset of Alzheimer's.

NIA has recently funded a Phase III randomized controlled trial designed to test the effects of a 3-year intervention of a hybrid of the Mediterranean and DASH diets, called MIND, on cognitive decline. This intervention will be tested among 600 individuals 65+ years of age without cognitive impairment who are overweight and have suboptimal diets that may place them at risk for developing dementia.

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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 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.

NIH-funded scientists developed imaging tools that are enabling a deeper understanding of how Lewy bodies form and contribute to neurodegeneration in mouse models of LBD. Additionally, they created animal and cell models with FTD-causing C9orf72 mutations to investigate how these mutations cause disease, and identified specific molecules in brain blood vessels that regulate beta-amyloid clearance.

In 2015, NIA supported a $21 million initiative to stimulate research on the immune and inflammatory mechanisms contributing to or mediating the development and progression of AD/ADRD. Scientists are studying the brain innate immune system and its crosstalk with the peripheral immune system to give greater insight into pathological processes underlying the disease.

In addition to continuing support for investigator-initiated research, in 2016 NIH released a request for applications (RFAs) to stimulate research on how vascular changes can cause disease within white-matter (areas of densely packed nerve fibers that carry information between brain regions), and plans to create a multi-center, interdisciplinary Center without Walls to investigate the molecular mechanisms of tau toxicity in FTD.

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Addressing Health Disparities. Race, 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 formal LTSS for those with dementia. A primary goal is to develop treatment and prevention strategies that are effective among diverse populations.

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NIA Enhances Information on Alzheimer's Clinical Trials Participation. NIA's the Alzheimer's Disease Education and Referral (ADEAR) Center developed a web mini-portal in 2015 for encouraging participation in Alzheimer's research. The portal features information on participating in Alzheimer's research, a newly upgraded AD/ADRD searchable clinical trial finder with user-friendly trial descriptions, and an infographic and social media messaging. ADEAR sends out monthly e-alerts to nearly 35,000 subscribers announcing new recruiting trials and featuring registries and matching services, such as the Alzheimer's Prevention Registry and Brain Health Registry.

In 2016, NIA joined a collaborative effort with Food and Drug Administration (FDA) and the PCORI-funded Alzheimer's and Dementia Patient/Caregiver-Powered Research Network to encourage research participation. The shared goal is to amplify the patient and caregiver voice in Alzheimer's and related dementias research and to broaden recruitment, especially among minorities.

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Recruiting Older Adults into Research Expands Recruitment Tools. Research cannot be conducted without the volunteers and their caregivers who make clinical trials possible. It is estimated that some 70,000 volunteers with Alzheimer's, mild cognitive impairment (MCI), or normal cognition are needed for clinical trials and studies; researchers will need to screen at least half a million potential volunteers to reach this goal. To address this need, the NIA, Administration for Community Living (ACL) and the Centers for Disease Control and Prevention (CDC) collaborate on Recruiting Older Adults into Research (ROAR), a program to promote research participation through outreach and messaging at the national, state, and local levels.

In 2015, the ROAR team continued to promote a toolkit of customizable materials for aging services and public health professionals to use in community settings and social media, and expanded the potential reach by translating materials into Spanish and Chinese. In addition, the group hosted a fourth annual webinar series for these professionals on Alzheimer's and caregiving resources, current research studies, and caregiver support programs that drew record attendance (500+ participants for each of three webinars) and offered continuing education credit.

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VA Targets Dementia Research. The U.S. Department of Veterans Affairs (VA) Office of Research and Development (ORD) has updated the wording in its specialty Alzheimer's Disease RFAs for biomedical laboratory or clinical research to include FTD, LBD, and/or VCID and dementia in addition to AD/ADRD.

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VA Collaborates with NIA. VA ORD is working with NIA to increase funding opportunity collaboration, including collaborating more closely on dementia research (e.g., recruitment/retention of participants in clinical trials; data sharing; biorepository use; and use of VA's electronic health records (EHRs) in research studies).

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