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Approved Concepts

Below are concepts approved at the most recent National Advisory Council on Aging (NACA) meetings. We have posted the approved concepts here to give interested researchers maximal lead time to plan projects. Please note that not all concepts will necessarily end up converting to a Funding Opportunity Announcement (FOA), and some of the concepts listed below (particularly from older Council meetings) may have already been converted to FOAs.

May 2022 Council

Approved concepts in this round:

Approved research and development contracts in this round:

Reissue of the Funding Opportunity Announcement: Integrative Research to Understand the Impact of Sex Differences on the Molecular Determinants of AD Risk and Responsiveness to Treatment

Alzheimer’s disease (AD) is a highly heterogeneous, multifactorial disorder. Approximately two-thirds of AD patients are women, and the biological basis of the sex-based differences in AD onset and progression remains elusive. A large body of evidence from clinical and laboratory research has demonstrated that sex differences are a major source of disease heterogeneity for many diseases including neuropsychiatric and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.

In recent years, large-scale systems biology approaches have enabled a better understanding of molecular mechanisms of AD stratified by sex. Sex-specific pathways and genetic interactions have been identified to contribute AD susceptibilities. However, the heterogeneity of Alzheimer’s and responsiveness to interventions remain underexplored at the mechanistic level. There remains a significant need for NIA to continue the support of this research area, to inform and drive the development of future precision medicine treatment/prevention for AD and related dementia (ADRD).

Given that fundamental issues regarding sex-specific phenotypes relevant to the heterogeneity of Alzheimer’s and responsiveness to pharmacological and non-pharmacological interventions remain underexplored at the molecular/mechanistic level, it is important to re-issue this funding initiative and continue the development of a robust cross-disciplinary research program.

This FOA will invite applications that employ integrative experimental and analytical approaches combining basic, translational, and clinical research aimed at developing a comprehensive understanding of the impact of sex differences on the trajectories of brain aging, phenotypes of AD and AD-related dementias (ADRD) risk, and responsiveness to pharmacologic and non-pharmacologic interventions. Of particular interest will be understanding the impact of sex-differences on the heterogeneity of brain aging, AD/ADRD across diverse populations, and the use of biosamples and data from AD/ADRD clinical trials to understand the impact of sex differences on the responsiveness to pharmacologic and non-pharmacologic interventions and to examine the molecular basis of this effect.

Scientific/Research Contacts

Jean Yuan, M.D., Ph.D.
Division of Neuroscience
Email Jean Yuan

Suzana Petanceska, Ph.D.
Division of Neuroscience
Email Susana Petanceska

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Geroscience Course

The field of Geroscience aims to slow the progression of age-related diseases and disabilities by learning how aging enables diseases and causes the accumulation of functional and clinical deficits. Geroscience includes a more holistic interpretation of older adult health that includes the behavioral, social, structural, and environmental influences on aging processes over the life course that shape health and disease trajectories and predict longevity.

The cross-disciplinary NIH Geroscience Interest Group (GSIG), held a summit in 2019 that highlighted the need to increase awareness of this area of research among stakeholders, introduce researchers to the field, create developmental materials and courses, and expand the expertise of the Geroscience workforce. To accomplish these goals, the GSIG proposes an FOA to support creative, short-term educational programs with a primary focus on courses that enhance and expand Geroscience skills and development at all levels of professional career development. Programs that increase diversity within the field and programs designed to educate the lay public across diverse communities would be encouraged. Furthermore, all programs supported through the proposed FOA would be expected to address how the approaches of Geroscience can inform our understanding of health disparities in aging.

The GSIG identified the following priority areas for the FOA:

  • Exposure to research in the Geroscience field, including coursework describing the interrelationships of the hallmarks of aging, chronic disease states associated with aging, behavioral and social determinants of health, health disparities, and interventions that extend lifespan and health span. This may include basic research on the biology of aging, as well as clinical and translational aspects of Geroscience.
  • Materials or approaches that improve the curation and dissemination of important Geroscience reviews, opinion pieces, and information about clinical trials in progress.
  • Opportunities for hands-on research experiences and networking with experts in the Geroscience field.
  • Activities and materials that promote awareness of Geroscience within the lay community.

Scientific/Research Contacts

Stacy Carrington-Lawrence, Ph.D.
Division of Aging Biology
Email Stacy Carrington-Lawernce

Siobhan Addie, Ph.D.
Division of Aging Biology
Email Siobhan Addie

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Estimating the Monetary Costs of Dementia in the United States Using NIA Funded Datasets

Dementia diagnosis is expected to triple in the next 30 years. As such, significant concerns exist over the cost of providing care and treatment for people living with Alzheimer’s disease and related dementias (ADRD). The United States currently lacks recent cost of illness estimates that are based on administrative, clinical, and survey data and whose basis for calculation are known to the scientific community. A transparent, fact-based estimate would support patients and their families as they understand and navigate the costs of dementia care; allow private entities to appropriately value the return on investment for care or cure innovations; and guide government decision-making around federal programs as well as long term cost projections given a variety of policy, care, and treatment innovation scenarios.

To meet these goals, this concept proposes a cooperative agreement to support the development and administration of a shared data source and lead the stakeholder engagement, total cost of illness modeling, and dissemination activities. The cooperative agreement will include support for administering the project, convening stakeholder and expert engagement committees, creating the project dataset based on linked datasets in the NIA enclave, modeling cost of illness, archiving the project dataset in the secure cloud computing environment, and publishing research findings. The project will also support pilots to examine the cost impacts of (1) specific, discrete advances (both pharmacological and non-pharmacological) in AD/ADRD treatment and prevention, and (2) simulations to model care and policy changes influencing access to, quality of, and uptake of AD/ADRD prevention and treatment. The selection of pilots will be influenced by the committee of third-party experts/stakeholders in conjunction with the Principal Investigator and NIA. The simulation studies will support and expand the representation of early-career researchers from the behavioral, social, economic, and data sciences who utilize the project dataset to engage in modeling and/or simulation research on AD/ADRD.

Scientific/Research Contacts

Priscilla Novak, Ph.D.
Division of Behavioral and Social Research
Email Priscilla Novak

 

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MEX-AD: MEX-AD: Clinical, Epidemiological, and Genetic Characterization of Alzheimer’s Patients in the Admixed Mexican Population

Having diverse participants can help researchers understand how dementia affects certain groups, why some communities are disproportionately affected by certain dementias, and which interventions may be most effective in particular groups. Hispanic people over the age of 65 in the United States account for the second largest population affected by Alzheimer’s disease and related dementias (AD/ADRD) with a prevalence rate of 12.2%. However, there are relatively few clinical, genetic, and biomarker studies focused on these populations.

The Center for Alzheimer’s Disease and Related Dementias (CARD) has a collaboration with University of California-San Francisco to expand ancestral diversification in AD/ADRD research. The goal for this proposed project is to establish a multi-cohort study in Mexico to characterize clinical, genetic, and phenotypic diversity in the Mexican population. The proposed project aims to build collaborative research efforts and engage local investigators to:

  • Address a critical gap in knowledge of how AD/ADRD develops and progresses in the admixed Mexican population across a network of 10 clinical sites across Mexico.
  • Provide a unique profile of risk factors, onset, and symptomology, which can be at least partly explained by genetic ancestry, and social, cultural, psychosocial, and environmental characteristics.

Note: All applicant questions should be directed to the contracting officer.

Contracting Officer

Karen Mahon
Office of Acquisitions, NIDA/NIA
Email Karen Mahon

Scientific/Research Contacts

Andrew Singleton, Ph.D.
Center for Alzheimer’s and Related Dementias (CARD)
Email Andrew Singleton

Mike Nalls, Ph.D.
Center for Alzheimer’s and Related Dementias (CARD)
Email Mike Nalls

Caroline Pantazis, Ph.D.
Center for Alzheimer’s and Related Dementias (CARD)
Email Caroline Pantazis

 

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Development and Maintenance of a Multigenotypic Aged Rat Colony

Basic biomedical research is supported by the National Institute on Aging through several programs which require animals as models of the aging process. Aged animals are not routinely available commercially, and most academic laboratories do not have the funds or facilities to raise aged animals. Consequently, NIA has established contracts for the supply of genetically defined, barrier-reared aged mice and rats for aging research.

This proposal is for a renewal of the contract for a long-term colony of aged rats. This resource is available to investigators funded for research relevant to aging by NIH, other government agencies, and not for profit organizations. The current colony consists of the following strains of rats, all ad lib-fed and group-housed: F344-CDF (Charles River Derived Fisher 344), BN/Crl (Brown Norway/Crl) and F344BN F1 (F344-CDF x BN/Crl). During the proposed contract, new stock of all strains will be rederived by the contractor from stocks that have been previously cryopreserved by the NIA, and breeding will commence to develop a new aged colony.

Note: All applicant questions should be directed to the contracting officer.

Contracting Officer

Karen Mahon
Office of Acquisitions, NIDA/NIA
Email Karen Mahon

Scientific/Research Contacts

Jennifer Fox, Ph.D.
Division of Aging Biology
Email Jennifer Fox

 

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Management of the Primate Aging Database

The Primate Aging Database (PAD) is a resource for investigators in the field of aging research, designed to facilitate the use of non-human primates (NHPs) as models of aging. The PAD collects data on normal aging in a wide range of NHPs. Sixty-seven metrics have been collected from healthy NHPs across their lifespan from 17 primate colonies across the United States as well as Puerto Rico and Germany. The PAD currently has approximately 1.2 million data points and the data can be used by the research community to identify changes in biological parameters with age, to validate NHP models for aspects of human aging, and to perform comparative analysis.

The proposed contract will maintain the PAD in the cloud, implement subject deidentification, solicit and add new data from NHP colonies/centers, enhance operability, update the user roster, provide technical assistance to users, and conduct outreach. Opportunities for enhancing the resource will be explored with the proposed contract renewal, including:

  • Increasing efforts to encourage data deposition from novel sources
  • Extracting data from the published literature and interfacing with existing data repositories
  • Expanding data fields to include imaging, -omics, immunological, and microbiome data collected by NHP researchers
  • Expanding analytical capabilities of the PAD
  • Improving the visibility of the PAD through outreach at scientific meetings
  • Initiating coordination between the NHP-Tissue Bank and the PAD

Note: All applicant questions should be directed to the contracting officer.

Contracting Officer

Karen Mahon
Office of Acquisitions, NIDA/NIA
Email Karen Mahon

Scientific/Research Contact

Jennifer Fox, Ph.D.
Division of Aging Biology
Email Jennifer Fox

 

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Development and Maintenance of a Non-Human Primate Tissue Bank

Biomedical research is supported by NIA through several programs that require studying aging in animal models. Non-human primates (NHPs) are important models for investigating the biology of aging, including the effects of environmental and social determinants. They also have the potential to provide data more directly translatable to human biology and aging.

The NHP Tissue Bank (NHP-TB) is a centralized bank of NHP tissue and serum for studies in aging research. The NHP-TB was initiated in 2003 and has been maintained through a contract. Its goals are to maximize the use of already available NHP biospecimens and provide a mechanism for multiple investigators to share tissue. The proposed contract will maintain and manage a collection of tissues and blood derivatives. Furthermore, it will expand the reach of the NHP-TB, improve coordination with NHP-holding  institutions and other tissue banks, increase the number of species and ages, and establish a registry of donors for efficient tissue collection.

Note: All applicant questions should be directed to the contracting officer.

Contracting Officer

Karen Mahon
Office of Acquisitions, NIDA/NIA
Email Karen Mahon

Scientific/Research Contact

Tiziana Cogliati, Ph.D.
Division of Aging Biology
Email Tiziana Cogliati

 

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Small Business Innovation Research (SBIR) Topics

This proposal will add three NIA topics to the NIH Parent SBIR contract solicitation PHS-2022. Use of the contract mechanism allows solicitation of topics that stimulate innovation and address unmet scientific priorities that are ripe for innovation while providing NIA with the ability to specify expected deliverables.

AI/ML Tool for Visualizing Behavioral and Social Science Research

Behavioral and social science research (BSR) can be conceptualized as a network of variables (characteristics of an individual, group, or environment) and the causal relationships between them. Currently, no tool exists that allows researchers to quickly derive a causal overview of BSR-specific literature. Developing an AI-based tool, specific to BSR, that can extract, aggregate, and visually map variables and causal relationships will allow researchers to explore the literature more in-depth and potentially uncover promising new associations between variables.

High Throughput Clonal Hematopoiesis of Indeterminate Potential (CHIP) Assay for Risk Stratification, Diagnosis, and Prognosis of Age-related Diseases

Many researchers are interested in understanding the role of clonal hematopoiesis and how it may affect health and age-related conditions and diseases. However, a low cost, scalable assay for analyses of clonal hematopoiesis does not exist. To help address this gap, this proposal aims to develop an inexpensive, high throughput assay to detect CHIP mutations for research purposes, which could eventually be translated into a diagnostic/prognostic assay for use in healthcare settings.

Improving Microphysiological Systems for AD/ADRD Therapy Development

There is a need for the development of more predictive, high-throughput in vitro microphysiological systems (MPS) as simple, reproducible, and scalable platforms that recapitulate organ-level functions to be used in different stages of AD/ADRD drug development. The proposed project aims to produce a system that is validated against known AD/ADRD therapeutic agents and align with human “omic” data from the Accelerating Medicines Partnership® Program for Alzheimer’s Disease to demonstrate the system's utility as a predictive tool and screening assay.

Note: All applicant questions should be directed to the contracting officer.

Contracting Officer

Karen Mahon
Office of Acquisitions, NIDA/NIA
Email Karen Mahon

Scientific/Research Contact

Jennifer Fox, PhD
Division of Aging Biology
Email Jennifer Fox

 

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January 2022 Council

Approved concepts in this round:

Broadening the Scope and Reach of NIA’s Resource Centers for Minority Aging Research (RCMAR) Program

Structural factors present barriers to full representation of individuals from diverse backgrounds in the NIA-supported scientific community, and especially in the behavioral and social sciences. Holistic approaches are needed more than ever to attract, develop, and retain a diverse population of aging researchers in the behavioral and social sciences and to cultivate future research leaders.

Now in its fifth cycle, NIA’s Resource Centers for Minority Aging Research (RCMAR) program is the Division of Behavioral and Social Research’s flagship mentoring program for scientists from historically under-represented groups who conduct behavioral and social research focused on aging, health disparities of older adults, and Alzheimer’s disease and related dementias (AD/ADRD). The recent growth of the RCMAR program, which more than doubled in size during the last funding cycle, affirms NIA’s longstanding commitment to promoting equity and inclusion in the aging research workforce. New strategies and infrastructure are needed to support this expansion and to foster the inclusion of researchers at Historically Black Colleges and Universities, Hispanic-Serving Institutions, Tribal Colleges and Universities, and other Minority-Serving Institutions.

To meet these goals, this concept aims to support new or renewal applications proposing: RCMARs that focus on behavioral and social science research, in a key area either related to aging, health disparities in older adults or both, and AD/ADRD RCMARs that focus on behavioral and social science research related to Alzheimer’s disease and related dementias. This concept also aims to support a single RCMAR Coordinating Center (CC), which through a cooperative agreement with NIA, will provide leadership for the RCMAR program.

RCMAR and AD/ADRD RCMAR Centers: NIA will solicit applications that retain the overarching two-fold goal and the basic structure of existing RCMAR (RFA-AG-18-003) and AD/ADRD RCMAR (RFA-AG-18-002) Centers, by including an Administrative Core, Research Education Component, Analysis Core, and an optional Community Liaison and Recruitment Core. All applications will be required to propose scientist-centered training and mentorship activities that serve to: 1) facilitate the development and enhancement of research skills, through the development and completion of a 12-18 month pilot research project; 2) strengthen team science and network collaborations; 3) enhance professional development skills; and 4) broaden the Center’s reach and impact through collaborative leadership with researchers at Historically Black Colleges and Universities, Hispanic-Serving Institutions, Tribal Colleges and Universities, and other Minority-Serving Institutions. Proposed activities will prepare RCMAR scientists to: 1) publish in high impact journals, 2) successfully compete for NIH’s small (R03, R21), large (R01) research grants, NIH Research Enhancement Awards (R15), or Career Development awards, in their dedicated research area, 3) contribute to the training of future scientists, and/or 4) address health disparities in clinical settings or via policy channels.

RCMAR CC: Responsibilities of the selected CC include: facilitation and coordination of communication among the RCMAR Centers; provision of logistical support to the RCMAR sites and to NIA; development and maintenance of a RCMAR CC website, which can serve as a repository of information and resources for the RCMAR program, extramural community, and public; development and dissemination of research resources and resources to address the professional development needs of minority faculty, including best practices for mentoring diverse faculty members and overcoming challenges in team science; organization of an annual meeting and symposia at scientific conferences; development or enhancement of infrastructure to track career development of RCMAR scientists; and formal evaluation of the RCMAR program.

Scientific/Research Contact

Melissa Gerald, Ph.D.
Division of Behavioral and Social Research
E-mail Melissa Gerald

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Demonstration Projects to Promote Use of Interoperable Health Records in Clinical Research

Electronic health records accumulate over time as people interact with health providers. For older adults, electronic health records often become fragmented, especially if they have seen multiple providers, relocated, or changed health plans. In research studies that focus on older adults with acute or chronic illness, study teams rely on information contained in health records immediately available to them, combined with self-report information to retrospectively construct patients’ medical histories. There often is little advanced notice prior to study enrollment, and limited opportunity for investigators to engage with patients to collect a medical history. Interoperable electronic health records collected from providers across health networks and geographic regions would permit study teams to gather a more comprehensive health history, allowing for better eligibility screening and more complete multifactorial analysis of research results. The 21st Century Cures Act Interoperability and Patient Access final rule (CMS-9115-F) created requirements for the healthcare industry to adopt standardized, interoperable, and secure downloadable, structured electronic health information at no cost. This new requirement will facilitate improvements in investigators’ ability to obtain historical medical information to be used as research data.

This concept is designed to provide evidence about the feasibility of utilizing the interoperability requirement to collect older research participants’ electronic health records. The projects are expected to exploit informatic approaches like natural language processing to summarize the content of the medical records to confirm eligibility for enrollment; acquire accurate, detailed information on comorbidities, and develop and evaluate informatic approaches to identify specific types of comorbidities relevant to the partner research study. The proposed FOA will support three-year demonstration projects to collect and analyze medical records from older adult research participants using downloaded health information. The applicants will partner with one or more newly funded or ongoing research studies that are enrolling new participants or reconsenting participants in established cohorts for follow-up visits. The projects will create a digital infrastructure to collect electronic health records donated by participants, and develop approaches to harmonize the data across patients and providers, and to develop informatic approaches to analyze the medical records.

Research/Scientific Contacts

Luci Roberts, Ph.D.
Division of Neuroscience
Email Luci Roberts

Marcel Salive, M.D., MPH
Division of Geriatrics and Clinical Gerontology
Email Marcel Salive

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Measures and Methods for Research on Family Caregivers for People Living with AD/ADRD

Family members — especially spouses and children — are the major source of unpaid care for older individuals living with Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). Changes in family structure and composition over the past several decades may have altered the role families play in caring for people living with AD/ADRD. Existing surveys and current measures and methods are limited in their ability to assess the diverse and often complex compositions of today’s families. In order to study the influence of demographic compositional changes in families and support the development of interventions and policies to support family caregivers of older adults living with AD/ADRD, it is critical to identify such family caregivers and what their needs are. Further, current studies may not capture differences in the criteria different groups (e.g., sexual and gender minority (SGM), minoritized, and immigrant individuals) use to define “family” (e.g., biological and/or legal ties, emotional closeness) and even what activities individuals consider to be caregiving. In addition, little is known about family members’ expectations and senses of obligation regarding caregiving — and what factors (including barriers and facilitators) predict whether these translate into actual caregiving given and received. These gaps in knowledge leave open unanswered questions about how to best support family caregivers and people living with AD/ADRD with (and without) such family caregivers.

This initiative addresses the pressing need for the development of measures and methods to assess who individuals consider family and what AD/ADRD caregiving tasks are expected or provided by family. Several large NIA-supported longitudinal studies (e.g., Health and Retirement Study (HRS), National Health and Aging Trends Study (NHATS), National Survey of Caregiving (NSOC), Panel Study of Income Dynamics (PSID), Add Health Parents Study) will be going back into the field and/or enrolling refresher cohorts in the next few years, presenting a potential opportunity to leverage existing data infrastructure. In addition, measures are needed to capture the experience of family caregiving in populations who are not currently well-represented in existing studies (e.g., SGM populations, immigrant groups, etc.) as efforts to enhance research in these populations grow.

Scientific/Research Contacts:

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
E-mail Amelia Karraker

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
E-mail Elena Fazio

Liz Necka, Ph.D.
Division of Behavioral and Social Research
E-mail Liz Necka

Melissa Gerald, Ph.D.
Division of Behavioral and Social Research
E-mail Melissa Gerald

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More Mobile Monitoring of Cognitive Change, Continued (M3C3)

The pathological processes related to Alzheimer’s disease and related dementias (AD/ADRD) may begin in midlife or earlier, sparking researcher interest in the measurement of even subtle neuropsychological changes in midlife. This proposed opportunity will extend work previously funded under RFA-AG-18-012 “Mobile Monitoring of Cognitive Change (U2C)," by addressing the need to add assessments of non-cognitive factors that may modify cognitive performance and enable widespread dissemination and support for use of the tools developed. This concept will extend previously funded work in the Mobile Toolbox Project, which involves two closely collaborating cooperative agreements designed to expand the range of contexts and frequency for cognitive assessment, resulting in more accurate estimates of cognitive variability and vulnerability. These tools include ultra-brief cognitive tests suitable for ecological momentary assessment and burst measurement designs that, over an extended period, allow the detection of very subtle cognitive changes as well as mobile app versions that can serve as replacements for traditional neuropsychological tests.

With an even greater interest in remote assessment due to the disruption caused the COVID pandemic, the opportunity will shift to the wide dissemination of the apps and infrastructure that have been developed to date in the collaborative Mobile Toolbox Projects. In addition, the existing infrastructure can be leveraged to support measurement of non-cognitive variables such as daily hassles, caregiving stressors, health challenges, health behaviors, and health systems interactions. There is also an opportunity to include real-time measures of affective, motivational, and social states and function and to develop linkages to the physiological data obtainable through passive sensors on mobile devices or attachable biosensors. Because the current projects build on well-documented app platforms, others will be able to develop and deploy instruments for their own studies and for use by others. This proposed single cooperative agreement will support the continued development of the platform with expanded content including non-cognitive measures and behavioral assessments, wider dissemination, and the ability for users to add study-specific measures.

Scientific/Research Contact

Dana Plude, Ph.D.
Division Behavioral and Social Research
Email Dana Plude

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NIA AD/ADRD SBIR/STTR Reissue: Advancing Research on AD/ADRD

The proposed initiative is a reissue of PAS-19-316 and PAS-19-317, Advancing Research on Alzheimer's Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD) (R43/44 and R41/R42 respectively; Clinical Trial Optional), which expires in September 2022. It supports applications through NIA's Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs to encourage research on and the commercialization of novel therapies, devices, products, and healthcare programs and practices to prevent the onset of AD/ADRD and to reduce their burden on individuals, their families, and society at large. Research areas supported through these initiatives include AD/ADRD prevention, diagnosis, treatment, care, and tools.

Scientific/Research Contacts

Zane Martin, Ph.D.
Division of Neuroscience
Email Zane Martin

Todd Haim, Ph.D.
Division of Extramural Activities
Email Todd Haim

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Neuronal Vulnerability to Proteinopathies in Alzheimer’s Disease and Alzheimer’s Disease Related Dementias

Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) impact specific brain areas, worsening with time and impacting more regions in a predictable fashion. However, it is unclear why the disease selectively affects certain regions of the brain e.g., the entorhinal cortex, hippocampus, and prefrontal cortex while other areas, such as the cerebellum, remain unaffected. Selective vulnerability refers to observations that subpopulations of neurons in different brain areas may be susceptible to specific pathological insults leading to cell dysfunction or death. Recent studies have shown that AD-related tauopathy begins in the locus coeruleus (LC), followed by neurofibrillary tangles in the entorhinal cortex, then hippocampal neurons, and then neocortical neurons. It is not yet understood why pathology appears where and when it does in the disease process. Current single-cell transcriptomics, epigenomics, and spatial transcriptomics technologies allow characterization of cell types at the molecular level at an unparalleled scale and resolution. This opens new research areas to define neuronal and/or glial cells’ vulnerability to AD/ADRD proteinopathies based on their molecular identity and allows for further development of mouse models that reproduce features of the pathology, and the identification of intrinsic properties of neurons vulnerable to AD/ADRD proteinopathies and provides information on vulnerable circuits and propagation paths. Understanding mechanisms underlying selective vulnerability from cells to networks in AD/ADRD is critical to define the disease process and develop effective therapies.

The goal of this concept is to define and characterize neuronal and glial cell populations that are vulnerable to AD/ADRD proteinopathies. Specifically, a subsequent FOA would solicit applications to: 1) establish a comprehensive set of data on neuronal and glial cells vulnerable to AD/ADRD proteinopathies based on single-cell transcriptomic or epigenetic signature; 2) identify intrinsic morphological, electrophysiological, and biochemical properties of neurons vulnerable to proteinopathies; and 3) identify neural circuits and/or large-scale networks that contribute to vulnerability to proteinopathies. To standardize sequencing, cell clustering and mapping methods, minimize variability, and maximize resource sharing, it will encourage a collaboration with investigators currently funded by the BRAIN Initiative. The proposed FOA will require that all data be placed in a comprehensive, common reference mouse brain atlas. It will leverage already existing technologies and tools such as single cell transcriptomics and epigenomics, novel models of AD/ADRD being developed by the MODEL-AD Consortium, and high resolution optogenetic fMRI or tissue clearing technologies that allow deep imaging of brain proteinopathies in 3D. This initiative will complement current NIA efforts aimed at a census of cells and circuits in the aging brain, the cellular scale connectome, and/or selective cell and network vulnerability in aging and Alzheimer’s disease.

Scientific/Research Contacts

Miroslaw “Mack” Mackiewicz, Ph.D.
Division of Neuroscience
Email Mack Mackiewicz

Brad Wise, Ph.D.
Division of Neuroscience
Email Brad Wise

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Optimization and Personalization of Diagnostic Tests for AD/ADRD in Older Adults with Multiple Chronic Conditions (MCCs)

The focus of this initiative is on the complex older patient who has MCCs and is being evaluated diagnostically for cognitive impairment or dementia. Persons newly diagnosed with AD/ADRD typically have other chronic conditions or geriatric syndromes (e.g., frailty) that can confound interpretation of traditional disease assessments. The ranges of “normal” for biomarkers and imaging metrics are often broader in older populations (where prevalence of MCCs reaches >85%) such that they overlap with abnormal values in younger persons, further reducing specificity. MCCs are also clinically significant in course, severity, and therapy with multiple medications, or polypharmacy. AD/ADRD studies of diagnosis and therapeutics have not adequately addressed differences by age and sex and have frequently excluded persons with a variety of comorbidities. Diagnostic testing is crucial for detecting new health conditions and selecting their treatments, yet test performance and clinical utility can shift with aging-related biological changes and in the context of MCCs. Biomarker- and imaging-based testing has become a major part of chronic disease management, including for AD/ADRD. The diagnostic criteria for several causes of dementia have been updated in recent years and are not yet well-adapted for clinical application. The accurate integrated assessment of MCC severity, risk factors, biomarkers, frailty, and cognition is necessary for a personalized medicine approach to AD/ADRD.

The proposed consortium will conduct transdisciplinary aging diagnostic biomarker and imaging research projects focused on AD/ADRD and MCCs to better align diagnostic testing with the needs and priorities of an aging population. It would also develop resources, assemble and analyze existing/available data and biobank resources, support pilot studies, conduct collaborative research, and integrate expertise. The consortium will:

  1. Assemble existing data and acquire real-world data to ensure large diverse sample with adequate representation of older adults with well-characterized MCCs and incorporate pre-specified subgroup analyses
  2. Analyze data for performance and accuracy of biomarkers (including blood, CSF, and imaging) in real-world older patients with MCCs
  3. Develop tools and methods to integrate MCCs and biomarkers into AD/ADRD care pathways.

Scientific/Research Contact

Marcel Salive, M.D., MPH
Division of Geriatrics and Clinical Gerontology
Email Marcel Salive

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Policy and AD/ADRD Healthcare Disparities: Access, Utilization, and Quality

This concept will support research that capitalizes on policy variations to address critical gaps in our knowledge of the processes that drive inequalities in health care access, utilization, and quality for people living with AD/ADRD in the community, assisted living facilities, and nursing homes. Policy can be defined to include “law, regulation, procedure, administrative action, incentive, or voluntary practice of governments and other institutions” (CDC Office of the Associate Director for Policy and Strategy). These can broadly include official national or federal laws and regulations as well as state, local, or institutional/facility-level policies and procedures. Creative methodological approaches that capitalize on policy variation (across time, place, etc.) are encouraged and might include quasi-experimental designs and natural experiments, propensity score matching, predictive modeling, geospatial modeling, qualitative inquiry, and innovative use of data linkage and big data (e.g., Centers for Medicare & Medicaid Services or commercial health services data). Investigators should propose a wide range of potential health and health care outcomes that will capture and explicate social disparities in access, use, and quality. Observational studies must go beyond describing disparities in AD/ADRD health care access, use, and quality to understand their underlying causes and mechanisms. Examples of relevant policy topics include but are not limited to CMS telehealth policy changes before and during the COVID-19 pandemic, state-level changes to LTSS coverage and practice (e.g., Oregon, Massachusetts, Wisconsin), changes to visitation policies in nursing homes and assisted living facilities.

Scientific/Research Contacts

Elena Fazio, Ph.D.
Division of Behavioral and Social Research
Email Elena Fazio

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
E-mail Amelia Karraker

Frank Bandiera, Ph.D.
Division of Behavioral and Social Research
Email Frank Bandiera

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Precision Medicine Approaches in Addressing AD/ADRD Minority Health and Disparities

Recent studies have revealed differences in neurobiological and neuropathological features and biomarkers associated with AD/ADRD among race and ethnic minorities, while others have noted no differences. Additional studies have noted differences in AD/ADRD risk among APOEe4 carriers of different ancestral backgrounds (e.g., elevated risk among Japanese compared to African-descent populations). African Americans and Latino populations experience higher prevalence of co-morbidities that are associated with vascular contributions to cognitive impairment and dementia. Similarly, there are behavioral and social risk factors for AD/ADRD that appear to operate differently or require additional characterization in minoritized populations. For example, although low educational attainment remains a risk factor for AD/ADRD in African Americans, differences in educational quality (while difficult to capture in existing measures) have been shown to moderate this relationship. There is also evidence that some neighborhood characteristics (including opportunities for social engagement and population composition) may be protective against dementia in minoritized populations, but these have not yet been well measured.

While some progress has been made in increasing our knowledge of the heterogeneity of AD/ADRD among minoritized populations, some populations remain severely under-represented in AD/ADRD research and very little is known about AD/ADRD within most of these populations. Additional research that captures neurobiological and neuropathological processes along with the environmental, sociocultural, behavioral, and demographic factors that often intersect with race and ethnicity within these populations is needed. In addition, low AD/ADRD incidence and prevalence among some minoritized populations can offer insights into protective or resilience factors associated with these diseases and may inform prevention or intervention strategies. Longitudinal studies that document and monitor trends in AD/ADRD prevalence and include both AD/ADRD neural biomarker(s) and rich behavioral or social assessment(s) are best positioned to inform our understanding of causal pathways driving AD/ADRD health disparities or prevalence. This initiative aims to:

  1. Support planning activities for the development or scale up of research infrastructure and resources to support studies of AD/ADRD in minoritized populations.
  2. Support pilot projects that utilize a multi-level, precision medicine approach and informs the scale up of future research.
  3. Support transformative multi-disciplinary teams to address AD/ADRD disparities, burden or resilience among minoritized populations.

Scientific/Research Contacts

Damali Martin, Ph.D., MPH
Division of Neuroscience
Email Damali Martin

Janine Simmons, M.D., Ph.D.
Division of Behavioral and Social Research
Email Janine Simmons

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Understanding the Supply of Professional Dementia Care Providers and Their Decisions

Global diagnosis of Alzheimer’s disease and related dementias is expected to triple in the next 30 years. There is a pressing need to understand how dementia care is supplied by various professional providers, and the influence it can have on the health care system, and as well as its effects on Persons with Dementia (PWD) and their caregivers in United States. PWD receive care from an array of paid care providers that include neurologists, geriatricians, psychiatrists, nurses, occupational therapists, social workers, certified nursing assistants, and home health aides. Across these care providers, training requirements and compensation vary, and there are different market conditions by region and payment models for services provided. Together, these factors shape the composition of the dementia care workforce size, expertise, tenure, and roles as well as care quality and access for PWD.

This concept will call for an internet survey of healthcare providers to understand how PWD are cared for by a wide range of professional providers, provide explanations for variation in the mix of providers providing care across regions, and elucidate how professional care team interactions influence care provision by the healthcare workforce on PWD. Specifically, it will produce a nationally representative sample of care providers that will include targeted oversamples to facilitate research on types of providers (e.g., neurologists, geriatricians, providers from underrepresented groups, etc.) and health systems that primarily care for underserved populations, including minoritized and rural populations. Projects will include linkages to administrative records (e.g., health care claims, Electronic Health Records, and payroll data) to connect participant responses regarding practice to data on health system actions and outcomes. The resultant data will enable the research community to explore the composition, qualities, and actions of this workforce to ensure challenges such as barriers to entry, retention, and the impact of an aging physician workforce can be addressed to support better care for the growing population of PWD.

Scientific/Research Contact

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
Email Partha Bhattacharyya

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September 2021 Council

Approved concepts in this round:

Cell Specific Impact of Liquid-Liquid Phase Separation in Aging and AD/ADRD

Protein aggregation has been a long-standing hallmark of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). For these conditions, there is a wide variety of proteins implicated in aggregation and disease, including such proteins as tau, TDP-43, and FUS. A common link between these proteins is that they all undergo liquid-liquid phase transitions (LLPS) to form biomolecular condensates (BMCs) under normal biological conditions to function properly. While classical organelles are surrounded by phospholipid bilayers, BMCs are membraneless organelles where proteins, RNA, DNA, and other cellular molecules are brought into close proximity to promote their interactions and to enhance their bioreactivity. Another factor that can influence BMC formation is the nuclear pore complex (NPC), which can transport proteins and nucleic acids in and out of the nucleus. The NPC has been shown to disaggregate proteins after aberrant BMC formation and can also impact the three-dimensional architecture of the genome to regulate gene expression. Despite an abundance of evidence connecting BMCs to neurodegenerative diseases, we still have a poor understanding of how BMC formation is regulated in different cell types and how different disease conditions may alter or influence normal BMC activity.

Emerging evidence has created a unique nexus between nuclear BMC function, cytoplasmic BMC function, the nuclear pore complex and how aging and neurodegenerative diseases may alter these normal functions. Many proteins that aggregate in AD/ADRD undergo transport in and out of the nucleus via the NPC, and the NPC has been shown to help disaggregate these proteins. Additionally, as aging occurs the NPC functions less efficiently, leading to improper transport in and out of the nucleus, which could lead to mislocalization of BMC associated proteins. Aging and cellular stress have also been linked to aberrant BMC formation and disease onset. Despite this growing evidence, there are still basic science questions to answer on how BMC formation is regulated within the cell and what makes certain cells or proteins more susceptible to aberrant BMC activity. For example, what types of modifications drive tau BMC formation and what changes occur to promote tau aggregation in AD? Furthermore, does tau form the same type of BMCs in different cell types or are there cell specific conditions that promote or dissolve BMC formation that may impact disease onset? The purpose of this concept and possible future funding opportunity announcement is to provide researchers an opportunity to gain preliminary data on how different cells or disease conditions may impact BMC formation, either cytoplasmic or nuclear, and what role the NPC may play.

Scientific/Research Contacts

Paul Barrett, Ph.D.
Division of Neuroscience
Email Paul Barrett

Viviana Perez, Ph.D.
Division of Aging Biology
Email Viviana Perez

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Coordinating Center for the Claude D. Pepper Older Americans Independence Centers

The Claude D. Pepper Older Americans Independence Center (OAIC) program supports centers of research excellence and research training leading to improved or maintained functional independence in older adults. The OAIC Coordinating Center facilitates interactions and collaboration among OAICs and serves as a conduit for translating OAIC objectives and findings. Functions of the OAIC Coordinating Center include developing and maintaining a website for scientific exchange, sponsoring the annual OAIC investigators’ meeting, sharing research resources, curating a registry of data, imaging and biospecimens from clinical aging research studies at OAIC sites, logistical and educational support for OAIC investigators, and advancing translation of OAIC discoveries. In addition to the functions described above, the OAIC Coordinating Center may also build on its existing efforts by:

  • Providing support to OAICs to facilitate compliance with NIH data sharing and clinical research policies
  • Improving the annual directory interface to enhance its use as a vehicle for collaboration
  • Expanding the scope and broadening participation in the annual OAIC investigators meeting
  • Expanding the registry of clinical aging research data, specimens, and imaging
  • Coordinating aging research consultation services across OAIC sites
  • Developing guidance for core measurement sets in clinical aging studies

Scientific/Research Contacts

Basil Eldadah, M.D.
Division of Geriatrics and Clinical Gerontology
Email Basil Eldadah

Winnie Rossi, M.A.
Division of Geriatrics and Clinical Gerontology
Email Winnie Rossi

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Cytosolic DNA Sensing as An Integrating Point of the Aging Hallmarks

Aging is a process that involves many cellular changes characterized by a set of molecular hallmarks. Since their discovery, studies have led to a comprehensive understanding of the individual aging hallmarks or associated pathways. However, the interactions of different aging hallmarks and whether those interactions are consequential for aging remain poorly understood. While cytosolic DNAs, a relatively newly identified hallmark, have been increasingly recognized as important players in aging, much about them remains largely unknown. In the past a few years, it has been well-documented that the accumulation of cytosolic DNA is associated with aging and cellular senescence and contributes to the deterioration of cellular and physiological functions.

This concept’s goal is to advance our understanding of cytosolic DNAs as an integrator of interactions among the aging hallmarks and as an instigator of the downstream cascade of events that lead to cellular senescence and inflammaging. This concept encourages researchers to collaborate for needed expertise, especially in the areas of new or advanced technologies that could be transformative in enabling researchers to address critical mechanistic questions relevant to cytosolic DNAs and aging hallmarks. This concept intends to cover the following topics:

  • Investigating the origins and identities of cytosolic DNAs, how they are generated and accumulated, and their associated changes in aging hallmarks.
  • Determining the additive or synergistic effects of different aging hallmarks on the accumulation of cytosolic DNAs, and vice versa.
  • Investigating whether there are any common or special features among the cytosolic DNAs of different origin and their relationship with different aging hallmarks.
  • Determining the causal or correlative relationship between the cytosolic DNAs and aging hallmarks – their temporal sequence and the threshold of these events that lead to cellular and physiological dysfunctions in aging.
  • Examine whether and how these cytosolic DNAs induce other signals, in addition to cGAS-STING pathway and SASP production, and contribute to the cellular dysfunction in aging.

Scientific/Research Contact

Max Guo, Ph.D.
Division of Aging Biology
Email Max Guo

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Health Equity and the Cost of Novel Treatments for Alzheimer’s Disease and Related Dementias

As the population with Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) grows, related health inequity and cost of care issues are of great concern. While racial and ethnic differences have been documented in the costs of AD/ADRD disease management, paid caregiving, and impacts of unpaid caregiving, less attention has been granted to quantifying the cost of treating Alzheimer’s disease with new medications or repurposed drugs and the health equity implications of access to such drugs. Failure to address the costs and benefits of new or repurposed pharmacological agents could lead to unnecessary delays in drug delivery.

This concept aims to support studies on the health equity implications of access to novel pharmacological treatments for AD/ADRD. It will support projects to conduct stakeholder engagement with underrepresented groups, followed by simulation modeling on the costs and health outcomes of new therapeutics in the U.S. population. Applicants will propose and apply methods to account for known racial and ethnic disparities treatment engagement and access. In the first phase, multidisciplinary teams will conduct rigorous stakeholder analysis with racial and ethnic sub-groups designed to understand the groups’ attitudes towards new drugs, and what outcomes are of most importance to the potential users of new drugs. In the second phase, the grantees will develop cost models and disseminate findings. This initiative will provide critical information to inform the design of access policies, such as co-payment and deductibles, for novel AD drugs. This effort will support and work to address drug access disparities in this area as these therapeutics transition to routine use.

Scientific/Research Contacts

Priscilla Novak, Ph.D.
Division of Behavioral and Social Research
Email Priscilla Novak

John Phillips, Ph.D.
Division of Behavioral and Social Research
Email John Phillips

Partha Bhattacharyya, Ph.D.
Division of Behavioral and Social Research
Email Partha Bhattacharyya

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Inter-organelle Communication as a Platform to Interrogate the Interactions of Hallmarks of Aging

Emerging evidence has pointed to organelle-organelle membrane contact sites as critical hubs for the transfer of ions, metabolites, lipids, and proteins between organelles and they have been shown to be involved in organelle biogenesis and dynamics. As inter-organelle communication is important in coordinating adaptative responses to intra- and extracellular stresses and maintaining cellular homeostasis, it is becoming clear that interactions between organelles undergo a cascade of decline in cellular aging. The biological hallmarks of aging, which have outlined major molecular and cellular processes that contribute to aging, have been studied primarily as processes of aging in isolation from each other. Inter-organelle communication provides a platform to interrogate novel interactions of aging hallmarks and associated mechanisms. Studies have begun to identify novel inter-organelle communication that can be understood as interactions of hallmarks of aging, however, additional research is needed to deepen our mechanistic understanding of the broad impact on cellular, tissue and organismal homeostasis. To date, much of the work on inter-organelle communication has been focused on identifying new contact sites and protein molecules involved in the interactions of apposing organelles in the context of physiology and disease. NIA aims to promote this nascent, exciting area of research on the extent of organelle communication that shapes the interactions of aging hallmarks.

NIA seeks comprehensive, multi-disciplinary research projects in the following areas:

  • Identification and characterization of novel organelle communication impacting the interactions of aging hallmarks
  • Evaluation of pro-longevity interventions in the context of direct or indirect organelle communication
  • Investigation of genetic and environmental factors involved in “re-wiring” of inter-organelle communication
  • Characterization of regulatory roles of inter-organelle communication in influencing the aging process at the organ and organismal levels
  • Development of systems-level imaging and microscopic technology to map organelle communication in aging relevant models (to provide information needed to drive more hypothesis-driven studies)

Scientific/Research Contacts

Yih-Woei Fridell, Ph.D.
Division of Aging Biology
Email Yih-Woei Fridell

Paul Barrett, Ph.D.
Division of Neuroscience
Email Paul Barrett

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Lipids in Brain Aging and AD/ADRD

Evidence for the important roles of lipids in brain aging and Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) has been building slowly for decades. Recent research has revealed a number of important insights related to altered lipid profiles and lipid turnover; the role of lipid droplets in neurodegeneration and normal aging processes; lipid metabolism and AD; and the role of lipid-rich white matter in learning and brain function. Yet, there is still much to be discovered about the implications of these findings and the role of lipids in brain aging and AD/ADRD. Addressing outstanding questions on lipids in the aging brain could lead to important insights into age-related decline and vulnerability to neurodegeneration and AD.

This concept aims to promote research that investigates outstanding questions regarding lipids in brain aging using approaches spanning from cellular and animal models to human studies, including:

  • The effect of lipid droplets on brain aging and AD, including whether their accumulation is pathological or protective;
  • The interaction of the periphery with lipids in the aging brain, including whether these could be targets for future biomarkers;
  • The influence of ApoE and lipid-mediated signaling on brain aging and AD/ADRD progression, including the effects of APOE status, other AD risk factors, and sex differences; and,
  • The contribution of myelin lipids and their signaling to brain aging and AD/ADRD.

Scientific/Research Contact

Amanda DiBattista, Ph.D.
Division of Neuroscience
Email Amanda DiBattista

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Mapping Interconnectivity Among Hallmarks of Aging Under Lifespan Modifications

The hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, were first described by López-Otín in 2013. Since then, there has been a significant amount of scientific evidence generated on the role of individual hallmarks on aging, and how they are involved in loss of function and the etiology of age-related diseases. Currently, it is a subject of ongoing research whether a specific hallmark by itself could be the primary driver of all aging phenotypes or if different combinations of interactions produce different aging phenotypes. Taken together, emerging evidence points to complex interactions as being the likely driver of aging. Lingering questions remain about whether there are hierarchies among the hallmarks that underlie different changes with age, or whether there is a threshold beyond which these hallmarks — and/or their interactions — overwhelm compensatory mechanisms and therefore become tipping points in the aging process.

This concept will solicit research projects to increase our understanding of the interactions among hallmarks of aging and their regulation in the following areas:

  • Characterization of the interactions among hallmarks of aging in various cells/tissues across the normal lifespan, to provide information about timing and priority (hierarchy)
  • Evaluation of whether the interactions between the hallmarks are an adaptive response to maintain health at different stages of life
  • Characterization of these interactions to determine if a threshold mechanism exists that leads to specific aging phenotypes
  • Investigation of which interaction(s) among the hallmarks is(are) necessary and sufficient to change the aging trajectory
  • Evaluation of the impact of lifespan-extending interventions on multiple hallmarks of aging at the single-cell level in different tissues as a means to uncover interactions from the onset of interventions started at different times over the life course

Scientific/Research Contact

Viviana Perez, Ph.D.
Division of Aging Biology
Email Viviana Perez

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Mechanisms of Brain Hypoperfusion in AD/ADRD

Cerebral blood flow (CBF) reductions are an early symptom of Alzheimer’s disease, and studies suggest that the severity of impairment in the CBF correlates with the severity of cognitive deficits. These observations have been replicated across a wide range of mouse models of AD. Despite the crucial impact of reduced blood flow in the brain (hypoperfusion) on cognitive symptoms and brain pathology in AD, there remains a limited understanding of the underlying molecular and cellular mechanisms and of the potential therapeutic benefit of CBF rescue. While some studies have investigated this question, there is a limited understanding of the molecular and cellular mechanisms underlying microvascular dysfunctions in AD. Since brain hypoperfusion exacerbates AD pathology and cognitive decline, it has been postulated that there is a vicious cycle of mutually reinforcing damage between β-amyloid-mediated pathology and CBF impairment; breaking this cycle by improving CBF could slow development and/or progression of AD.  Recent studies highlight both the importance of brain hypoperfusion in AD/ADRD and present some unanswered questions and controversies regarding cerebral blood flow in the context of neurodegenerative diseases. A deeper mechanistic understanding of changes in the cerebral blood flow in AD/ADRD could facilitate the development of innovative therapies for AD.

The goal of this concept is to understand the molecular and cellular mechanisms underlying the cerebral blood flow reduction in AD/ADRD. It will encourage studies of brain hypoperfusion in animal models of AD/ADRD, human studies which interrogate molecular and cellular mechanisms in association with hypoperfusion, as well as cellular models that recapitulate hypoperfusion in relation to neurodegeneration. If developed into a funding opportunity, this effort will solicit applications for projects designed to:

  • Determine the impact of blood brain barrier permeability on CBF and approaches to modulate vascular permeability in brain capillaries;
  • Establish mechanisms of pericyte constriction;
  • Understand leukocyte-endothelial interactions in the microvasculature;
  • Understand convergent causes and the interplay between different kinds of microvascular dysfunction in AD/ADRD;
  • Further develop cell-specific inducible knockout strategies to probe the involvement of different vascular and mural cells in CBF in the context of neurodegenerative diseases.

Scientific/Research Contact

Miroslaw “Mack” Mackiewicz, Ph.D.
Division of Neuroscience
Email Mack Mackiewicz

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Noncoding RNAs in Alzheimer’s Disease and Related Dementias

A large body of literature has shown that noncoding RNAs (ncRNAs) play crucial regulatory roles in multiple molecular and cellular processes. They are also emerging as an important player in the complex biology underlying neurodegenerative disorders, but their implication in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) remains largely unknown. Preclinical data indicate that targeting microRNAs could help reinstate protein homeostasis and memory function in AD, representing a new avenue for patient stratification and therapy. Despite growing interest in exploring ncRNA-based therapeutics and diagnostics, their pertinence as potential biomarkers and drug targets for AD/ADRD remains uncertain until we gain a systematic and deeper understanding of the biology of ncRNAs and how they regulate cellular and pathophysiological processes in diseases. There is enormous potential by targeting ncRNAs to identify novel mechanisms to inform the design of diagnostics and therapeutics.

This initiative is to stimulate research in noncoding RNAs to investigate the causality, directionality, mechanisms, and therapeutic potential of ncRNAs implicated in AD/ADRD. Specific research areas that of great interest include:

  • Characterize functional significance of ncRNAs in specific temporal and spatial contexts, in physiological and pathological conditions, and during disease stages of AD/ADRD.
  • Decipher causal roles of ncRNAs involved in pathogenic protein aggregation, neuroinflammation, and other pathophysiologic processes in AD/ADRD.
  • Identify targets (protein/DNA/RNA) ncRNAs interact with, and cell types and states ncRNAs operate in. Investigate functional outcomes of these molecular interactions.
  • Elucidate molecular and cellular mechanisms underlying alterations of ncRNAs implicated in the pathogenesis of cognitive decline and AD/ADRD.
  • Discover translational insights into ncRNA-based diagnostics and therapeutics to estimate AD risk, predict disease trajectory, improve patient stratification, and inform drug development.

Scientific/Research Contact

Alison Yao, Ph.D.
Division of Neuroscience
Email Alison Yao

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Pharmacokinetic and Pharmacodynamic (PK/PD) Studies of mTOR inhibitors on Aging-related Indications

Although rapamycin has been shown to prolong lifespan in the model organisms, including mammals, there are very limited preclinical and clinical data on the effects of other mTOR inhibitors on aging-related indications. Results from a few completed clinical trials on the effects of mTOR inhibitors on aging-related indications indicate some positive effects of these drugs on response to vaccination and viral infection in older persons. Overall, in doses used in these trials, the drugs were well tolerated. However, effects on clinical measures such as age-related chronic diseases, frailty, cognitive and physical performance, or self-perceived health have not been studied.

To advance research on these and other similar indications, there is an urgent need to address important gaps in pharmacokinetic and pharmacodynamic information on mTOR inhibitors in populations other than cancer patients, organ transplantation patients, or arterial stent patients. In these populations, mTOR inhibitors are generally given concurrently with other drugs or administered nonsystemically. Thus, there is limited knowledge of mTOR clinical pharmacology in conducting translational clinical trials for diseases and conditions associated with aging. Such information would enhance the ability to design future trials and interpret their results. Trials submitted in response to this opportunity will generate the much-needed data on pharmacokinetics and pharmacodynamics of different mTOR inhibitors in older adults who have, or are at risk for, diseases and conditions associated with aging. These data will be used to inform designs of future trials on the effects of mTOR inhibitors in older adults.

Scientific/Research Contact

Irina Sazonova, Ph.D.
Division of Geriatrics and Clinical Gerontology
Email Irina Sazonova

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Resources to Promote Coordination and Collaboration across Deeply Phenotyped Longitudinal Behavioral and Social Studies of Aging

NIA’s Division of Behavioral and Social Research (BSR) supports many deeply phenotyped, psychologically rich, small- to mid-size longitudinal studies which, collectively, span the full life course. The studies amass rich and wide-ranging data on behavioral and psychological processes related to personality, stress, emotion, social relationships, self-regulation, decision-making, and health behaviors to investigate the direct factors and mediators affecting health and well-being in later life. Many of these studies also collect detailed cognitive assessments, incorporate real-time experience sampling or daily diary protocols, and include biomarker and neuroimaging assessments. These approaches allow collection of precise and detailed data for hypothesis generation and provide opportunities for fine-grained mapping of individual trajectories of aging and life-span development. These smaller, longitudinal behavioral studies have been developed by independent investigators, utilize unique designs, and have been funded as stand-alone research projects.

In contrast to the nationally representative, population-based longitudinal studies supported by NIA, which have been successfully supported by research infrastructure that encourages coordination and collaboration, these smaller studies have not to date benefitted from such an infrastructure. As such, they represent an untapped resource.Establishing links across individual studies could address replication questions, allow findings to be extended to new contexts, and offer greater potential to identify important behavioral, psychological, and social factors that moderate healthspan and lifespan. This concept is designed to support research infrastructure to build collaboration and coordination opportunities across these smaller studies through activities such as:

  • Outreach to investigators and support for meetings that will stimulate collaborative work.
  • Methodological consultation services for investigators.
  • Creation of a publicly available web-based, meta-data catalogue to describe existing datasets, identify studies with overlapping measures or compatible designs, and support cross-project co-analysis.
  • Pilot support for collaborative teams to leverage existing studies to answer new questions, address replication and generalizability issues, and provide training for the next generation of investigators.

Scientific/Research Contacts

Janine Simmons, M.D., Ph.D.
Division of Behavioral and Social Research
Email Janine Simmons

Lis Nielsen, Ph.D.
Division of Behavioral and Social Research
Email Lis Nielsen

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Screening for Cognitive Impairment: Decision-making

In early 2020, the U.S. Preventive Services Task Force (USPSTF) released an “I Statement” summarizing their analysis of the benefits and costs of screening for cognitive impairment in older adults, concluding that more research is needed to make a recommendation for or against screening. That the evidence on this point is still considered inconclusive following a decade of investigator-initiated research on the topic suggests that a more programmatic approach will be required. Overall, the USPSTF concluded that “More research is needed on the effect of screening and early detection of cognitive impairment (MCI and mild to moderate dementia) on important patient, caregiver, and societal outcomes, including decision-making, advance planning, and caregiver outcomes.” NIA already supports a large and growing research portfolio both in the development of caregiving interventions as well as the society-level burden of dementia, with relatively much less work being done on individual level outcomes of the persons living with cognitive impairment. This concept seeks to fill the research gap by supporting the further development and validation of measurement tools that could be used to screen for deficits related to decision-making, planning, and other important outcomes and assess changes that could be useful in the context of future interventions. The target population for these tools will be persons who are or will be living with cognitive impairment.

In this area, the ability of research to provide useful evidence in either observational or interventional studies relies heavily on the quality and consistency of the outcome measures used. This project will focus on the development of a taxonomy of higher-level skills that support autonomy and daily life for people living with cognitive impairment, the creation of a more detailed mapping between those skills and daily life activities, and the design and validation of reliable and valid instruments to measure those skills. Future work can then develop and test interventions on those skills most amenable to intervention and determine whether earlier screening led to superior outcomes due to application of these interventions, thus also providing concrete evidence of the value of screening.

Scientific/Research Contacts

Jonathan King, Ph.D.
Division of Behavioral and Social Research
Email Jonathan King

Nina Silverberg, Ph.D.
Division of Neuroscience
Email Nina Silverberg

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Understanding Place-Based Health Inequalities in Mid-Life

The National Academies of Sciences, Engineering, and Medicine recently released “High and Rising Mortality Rates Among Working Age Adults,” a Consensus Study Report primarily supported by NIA’s Division of Behavioral and Social Research. The Study finds that recent declines in US life expectancy were the result of two mortality trends among the “working age” population (i.e., aged 25-64). First, working age mortality increased for drug- and alcohol-related causes and suicide beginning in the 1990s. Second, mortality declines in other causes of death, most notably cardiometabolic diseases, stalled among the working age population after 2010. This Study also identified large differences in life expectancy by place – i.e., U.S. Census regions, metropolitan areas, states, and counties. In many cases, place-based inequalities, including inequalities across the urban-rural continuum, have grown over the past several decades. These troubling domestic trends are coupled with declines in the nation’s life expectancy rankings, as life expectancy for both non-Hispanic whites and Blacks/African Americans have fallen further and further behind peer countries.

While the Consensus Study is rich in descriptions of levels of (and trends in) health inequalities by place, it does not provide definitive answers as to what social, economic, behavioral, and policy factors are responsible for these patterns. Understanding the fundamental causes of such inequalities — and the mechanisms through which they impact health — is essential to redressing them. Addressing place-based health inequalities requires data analysis and/or data infrastructure investments and enhancements to existing studies. As such, this concept proposes support for studies that will:

  1. Clarify the unique and interactive roles of social, economic, behavioral, and policy factors that drive place-based health disparities (levels and trends);
  2. Examine intersections between place and sociodemographic characteristics (e.g., gender, race, ethnicity, etc.) to better understand and address processes driving other health disparities; and/or,
  3. Include data collection and data enhancements to support the first two efforts.

Scientific/Research Contacts

Amelia Karraker, Ph.D.
Division of Behavioral and Social Research
E-mail Amelia Karraker

Frank Bandiera, Ph.D.
Division of Behavioral and Social Research
Email Frank Bandiera

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Understanding the Role of Bilingualism in Cognitive Reserve and Resilience in Aging and AD/ADRD

Bilingualism has been hypothesized to strengthen structural and functional connections in the aging brain in areas important for language and executive function. However, research findings in this area have been mixed and complicated by environmental and sociocultural factors like health equity in diverse populations, age of second language acquisition, aspects of language use, socioeconomic status, education, and recency of immigration. Better understanding of the complex interactions between neural, environmental, and sociocultural factors and the role of bilingualism in healthy aging and in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) may lead to new intervention targets and provide insight into the role of language in the aging brain. Lessons learned through this research could also help refine or develop interventions designed to build or stimulate cognitive reserve.

Given the unsettled state of research in this area, there is a need for more prospective, hypothesis-driven research to help build a theoretical framework and more clearly identify if and how bilingualism impacts brain function. In addition, multidisciplinary and multimodal approaches are needed to explore whether and how bilingualism exerts effects on cognitive reserve and resilience.

Scientific/Research Contacts

Matt Sutterer, Ph.D.
Division of Neuroscience
Email Matt Sutterer

Jonathan W. King, Ph.D.
Division of Behavioral and Social Research
Email Jonathan King

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May 2021 Council

Approved concepts in this round:

Diversifying the Therapeutic Pipeline for AD/ADRD: Drug Discovery for Novel Targets

The development of effective AD/ADRD therapies has proven to be difficult. One reason is that past AD drug development has been based on a narrow understanding of the disease centered on the amyloid hypothesis. In contrast to this conventional wisdom, growing amounts of new data suggest that clinical AD is a highly heterogeneous, multimodal, and multicomponent disease caused by a combination of genetic and environmental factors acting to perturb molecular networks across multiple interrelated biological pathways. These new discoveries, coupled with the failure of numerous anti-amyloid drugs, have highlighted the need for alternative therapeutic approaches that require the identification of next generation, nascent AD/ADRD drug targets. To improve and diversify the AD/ADRD drug development pipeline, the next generation targets must be preclinically validated, prioritized, and advanced into drug discovery campaigns.

To address the need for next generation AD/ADRD drug targets, NIA has spearheaded the launching of several target discovery initiatives (e.g. AMP-AD, M2OVE-AD, and Resilience-AD), which are aimed at discovering nascent, candidate therapeutic targets. Recently, NIA launched TREAT-AD for the development of target enablement packages (TEPs) for the characterization and experimental validation of these candidate drug targets. In 2016 NIA launched MODEL-AD, which is missioned to create and characterize late-onset AD (LOAD) mouse models that better recapitulate human LOAD.

This initiative will capitalize on the discoveries of AMP-AD and other target discovery programs, leverage the TEPs made available through TREAT-AD, and utilize the new LOAD models created by MODEL-AD for determining the efficacy of the emergent therapeutic agents in the most appropriate mouse model. The R61 will support feasibility studies (i.e., rigorous preclinical target validation) and R33 will support drug discovery/development of small molecules and biologics. In addition, the initiative will emphasize requirements for rigorous study design of preclinical efficacy testing studies and transparent reporting. If successful the initiative will improve, diversify, and reinvigorate the AD/ADRD drug development pipeline through the discovery of novel small molecule and biologic agents against preclinically validated, next generation drug targets.

Scientific/Research Contacts

Zane Martin
Division of Neuroscience
National Institute on Aging
Telephone: 301-827-7130
Email Zane Martin

Suzana Petanceska
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Suzana Petanceska

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Limited Competition: Renewal of the Caenorhabditis Intervention Testing Program (U01) and Its Data Coordinating Center (U24)

This FOA calls for renewal and scientific scope expansion of the Caenorhabditis Interventions Testing Program (CITP), a flagship program to support rigor and reproducibility in studies with laboratory animals. It aims to test potential intervention strategies that may moderate or alleviate health declines associated with aging across genetically diverse species and strains of Caenorhabditis (worms used to explore genetic and cellular mechanisms of longevity, learning and memory.) Interventions (compounds) are proposed for screening by the research community and then selected by an independent NIA-supported access panel of CITP.

This funding opportunity will use U01 (screening compounds) and U24 (Data Coordinating Center) mechanisms, inviting applications for a limited competition and set aside to achieve these objectives:

  • Lifespan Studies and Midlife Health Indicators. The CITP is expected to determine the effects of selected compounds on diverse species and strains of Caenorhabditis for lifespan extension and health benefits.
  • Reporters of Aging Hallmarks. The CITP is expected to develop reporters of key aging hallmarks in genetically diverse Caenorhabditis strains. These reporter strains will be used for screening of compounds.
  • Effects of Compounds Related to Alzheimer’s Disease or Related Dementias (AD/ADRD). Compounds may be nominated from screens against AD/ADRD. The CITP would test them under objectives 1 and 2, above, and a set of genetically engineered Caenorhabditis related to neuronal changes associated with AD/ADRD.

The goal of this program, as with the (mouse) Intervention Testing Program, is to establish “ground truths” about compounds that have robust effects on lifespan, or on hallmarks of aging, and provide accessible high-quality data potentially useful for novel hypotheses and which may spur further research in biology of aging.

Scientific/Research Contacts

Max Guo
Division of Aging Biology
National Institute on Aging
Telephone: 301-402-7747

Email Max Guo

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Reissue of the Alzheimer’s Drug Development Program

Alzheimer's disease is the most common cause of dementia in older people and is among the greatest healthcare challenges of the century. Delaying symptom onset by five years could reduce disease prevalence by as much as 50% and significantly reduce the disease’s health care costs and burden on families. Unfortunately, the clinically available therapies fall short of this requirement and provide only limited and temporary relief of symptoms. To avert this large and escalating public health crisis, new therapies that effectively prevent, slow the progression, or improve the symptoms of Alzheimer’s are urgently needed.

In 2006, NIA launched the Alzheimer’s Drug Development Program (ADDP) to address the unmet need for therapeutics, counteract the biopharma investment gap, and stimulate drug development. The ADDP is designed to offer academic and biotech researchers funding for drug development activities that can be conducted in their own laboratories, or in collaboration with contract research organizations that specialize in drug development activities. Between fiscal year 2007 and FY 2019, the ADDP funded 32 drug development projects. Of these, nine projects have transitioned to the clinic, with four in Phase I and five in Phase II. Since the end of FY 2019, an additional nine drug development projects have been funded through the ADDP. This concept calls for a reissue of the ADDP to continue to build on the gains made in the first fifteen years of the program.

Scientific/Research Contacts

Lorenzo Refolo
Division of Neuroscience
National Institute on Aging
Telephone: 301-594-7576
Email Lorenzo Refolo

Jean Yuan
Division of Neuroscience
National Institute on Aging
Telephone: 301-496-9350
Email Jean Yuan

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Small Business Innovation Research (SBIR) Research Contract Topics

This proposal will add three NIA topics to the NIH Parent SBIR contract solicitation PHS-2022. Use of the contract mechanism allows solicitation of topics that stimulate innovation and address unmet scientific priorities that are ripe for innovation while providing NIA with the ability to specify expected deliverables.

Geroscience-based Chronic Wound Treatment Product Development

Delayed wound healing increases the risk of recurrent infection and tissue necrosis, resulting in disability, hospitalization, and mortality among older adults. While NIA has regularly funded chronic wound healing product development, the ability to specify deliverables will ensure more optimal, geroscience-based wound healing SBIR grant applications. Development of wound treatments that incorporate modalities such as stem cell therapies, senolytics, or inflammation modulators can address the incidence of chronic wounds that do not follow a normal healing process and increase with age.

The Development of Mechanism-based Adult Stem Cell Treatments to Combat Aging Pathologies

There are now over 600 U.S. companies focused on stem cell-based treatments, yet there is a relative lack of mechanistic-based therapeutic discovery, which is critical for optimal development. This project will support research directed at developing mechanism-based therapeutics with defined alterations of cellular and/or molecular processes (senescence, inflammation, metabolism, DNA repair etc.) to facilitate aging tissue regeneration at the molecular, cellular, tissue, or organism level.

Improving CNS Gene Delivery Systems for AD/ADRD Therapy Development

There is a need for further efforts to specifically improve the safety and efficacy of gene delivery systems. Improved gene delivery systems are needed to overcome current challenges and better penetrate the blood-brain barrier, enhance stability and bioavailability, decrease immunogenicity, and improve cell-type targeting. As part of the AMP-AD initiative, this project will help improve, diversify, and reinvigorate the AD/ADRD drug development pipeline and may represent a key area for innovation.

Scientific/Research Contacts

Armineh Ghazarian
Office of Small Business Research
National Institute on Aging
Telephone: 301-827-6219
Email Armineh Ghazarian

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