Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Alzheimer’s disease (AD) is a highly heterogeneous, multifactorial disorder with a long prodromal period. The development of effective interventions to prevent or delay the onset of AD is critically dependent on gaining an in-depth understanding of how multiple etiologies and prodromal phenotypes lead to neurodegenerative changes that result in cognitive decline and dementia. A large body of evidence from clinical and laboratory research has demonstrated that sex differences help determine physiologic status and are a major source of disease heterogeneity for many diseases, including neuropsychiatric and neurodegenerative disorders such as AD and Parkinson’s disease.

Sex differences with regard to the risk of AD, vulnerability to ApoE genetic load, and severity of AD pathology burden have been established. Sex differences exist for many of the physiologic states and co-morbid conditions known to be risk factors for AD, such as inflammation, obesity, and cardiovascular diseases. In addition, multiple genes in the molecular processes/pathways involved in AD pathogenesis, such as brain bioenergetics, are located on the X-chromosome. Numerous animal model studies have pointed to multiple neuroprotective effects of estrogen and other sex steroids; however, evidence from clinical trials has been mixed and controversial.

Given that fundamental issues regarding sex-related phenotypes relevant to the heterogeneity of AD and responsiveness to pharmacological and non-pharmacological interventions remain underexplored at the mechanistic level, it is necessary to build cross-disciplinary research programs that will fill in the critical knowledge gaps and inform the development of precision medicine for treatment and prevention. The central goal of this initiative is to develop robust research programs that will explore how genes, environment, and host factors such as hormonal status (gonadal and brain-derived) interact at various levels of biologic complexity (i.e., cell, tissue, organs/organ systems, and populations) to produce heterogeneous phenotypes of disease risk and responsiveness to prevention/therapy in AD and AD-related dementias (ADRD).

Objectives

This Notice of funding opportunity (NOFO) invites applications that integrate experimental and computational approaches as well as basic and translational/clinical research towards a comprehensive understanding of the impact of sex differences on the trajectories of brain aging and disease, phenotypes of AD/ADRD risk and resilience, and responsiveness to pharmacologic and non-pharmacologic interventions. To this end, this NOFO encourages research focused on, but not limited to, the following areas:

• The impact of sex differences on the molecular trajectories of brain aging and on the molecular determinants of AD risk and progression across groups of varied racial, ethnic, and socioeconomic backgrounds.
• Molecular mechanisms underlying sex differences in brain bioenergetics, blood-brain barrier (BBB) and neurovascular unit function, myelin integrity, synaptic plasticity, and neural circuits integrity as they relate to the transition from healthy to pathologic brain aging/neurodegeneration.
• Molecular mechanisms by which sex differences influence differential vulnerability to metabolic, vascular, and inflammatory risk factors.
• Molecular mechanisms by which hormonal transition states (i.e., perimenopause, menopause, and andropause) influence the heterogeneity of AD risk and AD progression.
• Understanding how sex interacts with different ApoE genotypes to influence the molecular mechanisms of brain aging, AD risk phenotypes, and responsiveness to treatment.
• Molecular determinants of sex differences in responsiveness to pharmacologic and non-pharmacologic treatment of AD/ADRD.

A cross-disciplinary team-science approach that brings together experts in neuroscience, physiology, computational biology and data science, and translational and clinical research is strongly encouraged, as is the integrative use of human data and biosamples with cell-based and animal models.

This NOFO encourages studies that integrate and analyze multimodal data, such as multi-omics, imaging, and clinical data, as well as electronic health records and digital health data from biosensors or smart devices. Of particular interest are projects that use biosamples and/or data collected from prior or ongoing clinical trials to assess sex differences in response to interventions and to examine the molecular basis of this effect.

This NOFO will support mechanistic clinical trials, defined by the NIH as including studies designed to understand a biological or behavioral process, or the pathophysiology of a disease process, through manipulation of that process, or to understand the mechanism of action of an intervention (see NOT-OD-15-015).

Applicants are strongly encouraged to contact NIA Scientific/Research staff early in the pre-submission process to ensure that their application is responsive to the programmatic goals of this NOFO.

Non-responsiveness Criteria

• Research that relies solely on the use of cell-based and animal models will be considered non-responsive to this NOFO and will not be reviewed.
• Studies whose purpose is to evaluate safety; clinical efficacy, effectiveness, and management; and/or implementation of new interventions will be considered non-responsive to this NOFO and will not be reviewed. The National Institute on Aging (NIA) supports clinical trials focused on safety, efficacy, and effectiveness under  PAR-23-081.

Applicants are expected to follow open-science, open-source principles and adhere to NIH guidelines for rigorous study design and transparent reporting to maximize the reproducibility and translatability of their findings. Please refer to the Resource Sharing Plan section of this NOFO for detailed guidance.

Responsive applications should include appropriate support for curation and annotation of the molecular and clinical data types used and/or generated on the project to maximize the usability of the data by the broader research community.

All studies should be conducted and reported in compliance with NIH guidance on rigor and reproducibility. In particular, investigators proposing animal model studies are expected to follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies.

Although animal models can hold promising potential to advance translational efforts, the specific rationale for their use must be sufficiently justified, and compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (Policy) is an absolute requirement. All institutions are required to comply, as applicable, with the Animal Welfare Act, and other Federal statutes and regulations relating to animals.

NIA supports a central resource to NIA staff and extramural investigators to facilitate/support the conduct and management of clinical research. This resource, the Clinical Research Operations Management System (CROMS), is a comprehensive data management system to support the business functions, management, and oversight responsibilities of NIA grants that support the conduct of clinical research with human subjects. It is the expectation by NIA that all successful applicants will interface, integrate, or adapt their information system(s) and processes to interact with existing and future components of the CROMS as necessary, including the use of CROMS data templates as specified.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of the proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Suzana Petanceska, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: petanceskas@nia.nih.gov

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

For animal model studies, applicants must outline the study design and data reporting plans explaining how they are in compliance with the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies (if applicable).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

In keeping with NIA’s strategic goal to enable and promote open science practices,  to enhance transparent reporting, and to increase research rigor and reproducibility, awardees must make all resources (e.g. analytical methods and pipelines, network models,  research tools, cell lines and animal models) available to the broad scientific community via the NIA-supported AD Knowledge Portal, or NIH-designated repositories.  

In keeping with the open science aspect of this funding initiative, the following will be expected from the recipients:

• All analytical methodologies, tools and pipelines, network models will be made fully reproducible and transparent so that results can be vetted and existing analysis techniques can be quickly applied to new application area.
• All models of biological systems and networks will be openly available to users such that theoretical predictions can be rapidly validated experimentally.
• All disease models (cell lines and animal models) generated during the project will be made freely available to qualified investigators to accelerate their characterization, validation, and translational utility.
• All biological samples used to generate data with this award will be made available to all awardees of this initiative and to other qualified investigators.

Awardees will be expected to have all resources (e.g. analytical methods and pipelines, network models, research tools, cell lines and animal models) deposited in the AD Knowledge Portaland/or other NIH-designated repositories.   Awardees are expected to make all resources available after they have undergone quality control (no later than 6 months after resource generation). There will be no embargo imposed on the use of such resources after they have been made available through these repositories. Program staff may negotiate modifications to the plan prior to funding. 

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

In keeping with NIA’s strategic goal to enable and promote open science practices and FAIR (Findable, Accessible, Interoperable, and Reusable) data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, awardees must make all data available to the broad scientific community via the NIA-supported AD Knowledge Portal or through other NIH-designated repositories. 

In keeping with the open science aspect of this funding initiative, all data sets used/generated on the project (such as data about phenotypes and high-dimensional omic data, including genomic, proteomic, and metabolomic data generated from cell-based and animal models) will be made accessible and reusable by qualified individuals other than the original data generators to enable multiple parallel approaches to data analysis and interpretation.

 As part of a complete Data Management and Sharing plan, applications must provide a plan and timeline for data generation, reporting and deposition. Applicants should include appropriate support for annotation and curation of the molecular and phenotype data used and/or generated on the project to maximize the usability of the data by the broader research community. Program staff may negotiate modifications to the plan prior to funding.

All data and data-related results generated from animal model studies, including both negative and positive findings, are expected to be incorporated in NIA's Alzheimer's Disease Preclinical Efficacy Database Portal (AlzPED) no later than 9 months after study completion or at the time of first manuscript publication, whichever comes first. Published studies will be incorporated in AlzPED as a curated record; unpublished studies will be incorporated in AlzPED as a citable pre-print.

Recipients will be expected to have all data and data-related analytical results deposited in the AD Knowledge Portal and/or other NIH-designated data repositories after they have undergone basic quality control (within 3 months of data generation completion). Data shared via the AD Knowledge Portal will be made broadly available twice a year and no later than 6 months after deposition.  There will be no publication embargo imposed on the use of data after they have been made available through the AD Knowledge Portal or other data repositories.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed..

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

All studies should be conducted and reported in compliance with NIH guidance on rigor and reproducibility. Particularly, preclinical efficacy studies must follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies.

Applicants must follow open-science, open-source and FAIR principles and adhere to NIH guidelines for rigorous study design and transparent reporting to maximize the reproducibility and translatability of their findings.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIA, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Following open-science, open-source principles and adhere to NIH guidelines for rigorous study design and transparent reporting, in compliance with NIH guidance on rigor and reproducibility.
• How well animal model studies follow the general ARRIVE guidelines for rigorous animal research and the best practices guidelines for AD preclinical efficacy studies.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

Defining the details for the projects within the guidelines of this NOFO. The PD/PI will agree to accept the close coordination, cooperation, and participation of the NIH staff (Project Scientists) in those aspects of scientific and technical management of the projects as described below. Specifically, the PD/PI(s) supported by this initiative will do the following:

• Retain the primary authority and responsibility for the project as a whole, the development of methods and procedures to accomplish the aims and objectives of the NOFO, and the preparation of publications.
• Report progress on annual milestone(s) as well as other relevant information to the NIH Project Scientist(s) or Program Officer(s) in addition to the standard annual progress reports (see Section VI.3. Reporting), and coordinate and cooperate with NIH staff and other members of the appropriate collaborating NIH programs.
• Work directly with the NIH Project Scientist(s) on the coordination of intra-program activities and the integration of individual projects within the 'Impact of Sex Differences on AD/ADRD Consortium' as well as with other relevant NIH programs.
• Participate in the 'Impact of Sex Differences on AD/ADRD Consortium' in person and budget for travel to annual joint meetings held once annually with other critical staff.
• Participate in the appropriate coordinating meetings, working groups, and/or teleconferences as needed.
• Agree not to disclose confidential information obtained from other members of the 'Impact of Sex Differences on AD/ADRD Consortium' and its extended research network.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

One or more designated NIH Program Staff members, acting as Project Scientists, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The role of the Project Scientist(s) will be to facilitate and not to direct. Specifically, the NIH Project Scientist will do the following:

• Provide technical assistance and advice to the awardee to achieve the aims of the cooperative agreement, as appropriate.
• Work directly with the awardee to facilitate their interactions within the 'Impact of Sex Differences on AD/ADRD Consortium'.
• Promote and help coordinate collaborative efforts that involve interactions with other members of the AD-translational research community, as well as with other NIH-sponsored programs, projects, and centers, where appropriate.
• Assist in the interaction between the awardee and investigators at other institutions, as appropriate for the program.
• Assist in avoiding unwarranted duplication of effort.

To help carry out these duties, Project Scientists may consult with non-NIH experts in the field.

The NIH Project Scientist(s) will perform the initial analysis of awardee milestones and will work with the Program Officer on any milestone renegotiations.

Additionally, an NIH Program Officer will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. In addition, the NIH Program Officer will have the option to recommend, following consultation with the NIH Project Scientist(s), the withholding or reduction of support from any project that substantially fails to achieve its goals according to the milestones agreed to at the time of the award.

NIH reserves the right to withhold funding or curtail an award in the event of substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or ethical or conflict of interest issues.

Areas of Joint Responsibility include:

The NIH Project Scientist(s) and the PDs/PIs of the 'Impact of Sex Differences on AD/ADRD Consortium' will be jointly responsible for the coordination of intra-program activities and the integration of individual projects with other appropriate NIA and NIH programs. Joint responsibilities include the following:

• Developing working groups and/or coordinating committees and trans-project efforts, as needed.
• Organizing and conducting regular meetings to share progress and foster collaborations between members of the 'Impact of Sex Differences on AD/ADRD Consortium' either by teleconference, videoconference, or face-to-face, as needed.
• Organizing workshops to promote outreach.
• Convene to assess progress, discuss data resources, establish priorities, consider policy recommendations, propose publication guidelines, and discuss strategies.
• Meet in person, virtually, or by teleconference, with additional project staff and/or NIH staff, on a schedule to be determined.
• The NIH Project Scientist(s) may form an External Scientific Panel (ESP) composed of senior non-federal scientists who are not directly involved in the activities of the 'Impact of Sex Differences on AD/ADRD Consortium'. The ESP would advise NIH on the progress of the Consortium milestone deliverables, on the contributions of individual projects and/or project collaborations within the consortium, and on the progress and effectiveness of the consortium as a whole.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

In keeping with NIA’s strategic goal to enable and promote open science practices and FAIR (Findable, Accessible, Interoperable, and Reusable) data practices, and the NIA/NIH goal to enhance transparent reporting and increase research rigor and reproducibility, awardees must make all data available to the broad scientific community via the NIA-supported AD Knowledge Portal or through other NIH-designated repositories.

In keeping with the open science aspect of this funding initiative, all data sets used/generated on the project (such as data about phenotypes and high-dimensional omic data, including genomic, proteomic, and metabolomic data generated from cell-based and animal models) will be made accessible and reusable by qualified individuals other than the original data generators to enable multiple parallel approaches to data analysis and interpretation. 

As part of a complete Data Management and Sharing plan, applications must provide a plan and timeline for data generation, reporting and deposition. Applicants should include appropriate support for annotation and curation of the molecular and phenotype data used and/or generated on the project to maximize the usability of the data by the broader research community. Program staff may negotiate modifications to the plan prior to funding.

All data and data-related results generated from animal model studies, including both negative and positive findings, are expected to be incorporated in NIA's Alzheimer's Disease Preclinical Efficacy Database Portal (AlzPED) no later than 9 months after study completion or at the time of first manuscript publication, whichever comes first. Published studies will be incorporated in AlzPED as a curated record; unpublished studies will be incorporated in AlzPED as a citable pre-print.

Recipients will be expected to have all data and data-related analytical results deposited in the AD Knowledge Portal and/or other NIH-designated data repositories after they have undergone basic quality control (within 3 months of data generation completion). Data shared via the AD Knowledge Portal will be made broadly available twice a year and no later than 6 months after deposition.  There will be no publication embargo imposed on the use of data after they have been made available through the AD Knowledge Portal or other data repositories.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Shreaya Chakroborty, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-827-4019
E-mail: shreaya.chakroborty@nih.gov

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Phone: 301-402-7700
Email: ramesh.vemuri@nih.gov

Jillian Morris
National Institute on Aging (NIA)
Telephone: 301-496-8986
Email: morrisjil@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.