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Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov)

Components of Participating Organizations
National Institute on Aging (NIA) (http://www.nia.nih.gov)

Title: International network for identification, evaluation, and follow-up of families with early onset dominantly inherited Alzheimer’s disease (U01)

Announcement Type
New

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number: RFA-AG-08-002

Catalog of Federal Domestic Assistance Number(s)
93.866

Key Dates
Release Date: July 17, 2007
Letters of Intent Receipt Date(s): September 19, 2007
Application Receipt Date(s): October 19, 2007
Peer Review Date(s): January/February 2008
Council Review Date(s): May 2008
Earliest Anticipated Start Date(s): July 1, 2008
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: October 20, 2007

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Purpose. The purpose of this announcement is to solicit U01 cooperative agreement applications that will set up an international network consisting of a consortium of scientific investigators that will have the responsibility to identify, recruit, evaluate, and follow-up individuals from families with early onset dominantly inherited Alzheimer’s disease [i.e., families with the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) mutations or duplications or others still to be discovered].

Special receipt date is October 19, 2007

Initial merit review convened by NIA

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

The purpose of this announcement is to solicit U01 cooperative agreement applications that will set up an international network consisting of a consortium of scientific investigators that will have the responsibility to identify, recruit, evaluate, and follow-up individuals from families with early onset dominantly inherited Alzheimer’s disease [i.e., families with the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) mutations or duplications or others still to be discovered].

Background

Rare cases of Alzheimer disease (AD), with an autosomal-dominant pattern and an early onset, are inherited. Autosomal-dominant, early-onset AD is a heterogeneous disorder that is caused by mutations in three different genes; the amyloid precursor protein (APP) gene on Chromosome 21, the presenilin-1 (PS-1) gene on Chromosome 14, and the presenilin-2 (PS-2) gene on Chromosome 1. Approximately half of autosomal-dominant AD cases are associated with mutations in the PS-1 gene, whereas mutations in the PS-2 and APP genes represent less frequent causes. There is considerable allelic heterogeneity in autosomal-dominant AD, and approximately 190 different mutations have been described in independent families thus far (157 PS-1, 10 PS-2, and 27 APP mutations). In comparison to other genetic disorders caused by a single genetic defect, this heterogeneity confers some clinical and biological variations to each mutation. However, these mutations share some common phenotypic features: an onset generally before age 60 (mean age at onset is 44 46 years for PS-1, 58 59 years for PS-2, and 49 years for APP mutations, although some people can become clinically affected as young as 30 years of age), and an autosomal-dominant pattern of inheritance. Also, these mutations alter the normal processing of the APP protein and increase the production of A 42(43) in brain, plasma, transfected cells, and transgenic mice.

Early onset dominantly inherited AD accounts for less than 1-5 % of all cases of the disease. However, these individuals develop a similar pattern to the more common late onset form of the disease of insidious onset and progressive decline that initially affects episodic memory and is then followed by global cognitive dysfunction. There are also pathological and biochemical similarities between familial and late onset AD including atrophy of whole brain and hippocampus assessed by magnetic resonance imaging (MRI) that predates the clinical diagnosis of AD; changes in brain metabolites (N-acetyl aspartate, myo-inositol, creatinine) in posterior cingulate assessed by magnetic resonance spectroscopy (MRS) that are detectable at a very early preclinical stage of AD; decreased glucose utilization assessed by PET in presymptomatic individuals; and high amounts of brain A 42 deposits, as well as other brain pathologies common to early and late onset AD. Because individuals possessing these mutations are destined to develop AD, and families with a given mutation develop symptoms at a relatively predictable age, such individuals may be studied from a presymptomatic stage and thus provide a unique opportunity to investigate the very earliest manifestations of AD. Also, because these mutations increase the production of A 42 in the brain, it is reasonable to hypothesize that this would be the best group in which to determine whether biological or pharmacological agents that reduce A 42 brain levels may have a therapeutic or protective effect. In contrast to persons with early onset disease, patients with late onset disease are often suffering from age-related comorbidities that may make the correlation between reduction of amyloid load and cognitive change less apparent.

Thus, the advantage of studying the early onset dominantly inherited AD cohort is the certainty of diagnosis, the reduction in age-related comorbidities, and the feasibility of assessment from a presymptomatic stage. There is also the presumption, but not the certainty, that the information about the brain mechanisms of disease, including evaluation of imaging and biomarkers, as well as the results of intervention studies in this group of early-onset AD individuals, would also be relevant to late-onset disease. The disadvantage is that there are relatively few of these individuals, and they are scattered around the world. These issues constitute the reason that individuals from early onset dominantly inherited AD cohorts have largely been blocked from participation in most clinical studies and trials even though, from anecdotal information that investigators have received, these individuals are very interested in being included in this research. With the development of new methods for imaging amyloid in the brain of living people and drugs targeting amyloid production (e.g. secretase inhibitors), studying this group is even more scientifically valuable. As indicated previously, because all of these mutations have the effect of increasing the production of A 42 in the brain, it is reasonable to hypothesize that this would be the best group in which to determine whether biological or pharmacological agents that reduce A 42 production, accumulation, or clearance may have a therapeutic or protective effect.

An essential feature of this initiative is that the clinical, neuropsychological, imaging, and biological data and samples will be placed in the public domain and made available to all qualified scientific investigators by methods and at time intervals to be determined by the Steering Committee.

The protocols used in this study should be consistent with those developed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI; http://www.loni.ucla.edu/ADNI) for data and sample collection, storage, and analysis.

Scope and Objective

The objective of this announcement is to solicit cooperative agreement applications that will set up an international network consisting of a consortium of scientific investigators that will have the responsibility to identify, recruit, evaluate, and follow-up individuals from these families in which early onset dominantly inherited Alzheimer s disease is found. It is anticipated that this network will include at least one performance site outside of the United States. Applicants in response to this FOA should propose a research design for a network that will allow collection and coordination of data on individuals from affected families. The aim of the network is to facilitate use of the data generated from these families in order to provide key information on understanding the initiation and progression of early onset dominantly inherited Alzheimer s disease. The expected structure of the network would include a coordinating center; various cores/functions, such as a clinical core/function, a neuroimaging core/function, a biomarker core/function, a genetics core/function, a neuropathology core/function, a bioinformatics core/fundction, a biostatistics core/function; and national and international clinical sites. It is expected that the application will provide a process for identifying the relevant families and individuals and recruiting them into the study and determining the protocols for clinical/neuropsychological, neuroimaging [e.g., MRI, PET (FDG, amyloid imaging)], genetic, biomarker (blood, CSF), and neuropathological evaluations. Applicants must justify their particular choice of markers, procedures, and protocols. All of these evaluations must be done in a consistent manner across all the sites. The timing of follow-up evaluations needs to be provided. Also, the procedures and protocols for data and sample acquisition, processing, storage, and analysis must be discussed, as well as a method for sharing the data and samples with the scientific community in a timely fashion. All of the protocols should be consistent with those developed for the Alzheimer’s Disease Neuroimaging Initiative (ADNI; http://www.loni.ucla.edu/ADNI).

The coordinating center will be responsible for delineating protocols; setting up, coordinating, and monitoring recruitment and retention activities; organizing and monitoring data and sample collection, storage, and distribution; and other administrative functions such as organizing Steering Committee meetings. It is estimated that approximately 200-300 participants will be recruited and followed. The application should describe how the coordinating center will provide genetic counseling for the participants. It should also show how the structure and organization of the cores/functions enables and facilitates recruitment, data collection, analysis, and sharing. In addition to the coordinating center, a likely organizational structure would have a clinical core/function responsible for developing and monitoring the clinical and neuropsychological evaluations; a neuroimaging core/function responsible for delineating imaging protocols, establishing and monitoring quality assurance (QA) and quality control (QC) procedures for the collection of imaging data among the sites, storage and distribution of imaging data, and image processing; a biomarkers core/function responsible for determining the protocols for collection, transport, and storage of the blood and cerebrospinal fluid samples and the determination of which molecules to analyze (e.g., A and tau/phospho-tau in CSF); a genetics core/function responsible for the collection and analysis of DNA, making and storing transformed cell lines, and any genetic/genomic studies; a neuropathology core/function responsible for determining the protocols that will be used for reliable cross-site post-mortem collection and analysis of the brains of those participants who die during the course of the study; a bioinformatics core/function responsible for storage of the various types of data and dissemination of the data to investigators in a user-friendly way (e.g. through a searchable web site); and a biostatistics core/function responsible for analysis of the longitudinal data within, between, and among the various data domains. The responsibilities of any other proposed cores/functions should also be delineated in the application. Each clinical site should provide a core team of researchers skilled in the recruitment and clinical evaluation of these subjects. All sites must also have MRI capability and access to adequate time on an MRI scanner; a subset of sites must have capability and access to adequate time on a PET scanner. Individual potential clinical sites may be included in more than one application.

The coordinating center is expected to work in collaboration with the various cores/functions, the clinical sites, and the NIA project scientist to assist in protocol development and planning; subject recruitment, retention, and follow-up; and project administration.

A steering committee composed of the principal investigator, the leaders of the various cores/functions, the investigators in the network, a bioethicist, a family representative, an FDA representative, and appropriate NIA staff will coordinate the work of the consortium, including responsibility for finalizing the standard definitions, procedures, and measures for all the protocols.

To advise the Steering Committee, applicants should also plan to recruit an external advisory committee, consisting of scientists from outside the institutions awarded funding for the network. External advisory committee members should not be recruited until the NIH review is complete. This committee will be used to evaluate progress, ensure that data monitoring procedures are sufficient and that quality data are being collected to the highest standards possible, evaluate the effectiveness of communications among the coordinating center, the cores/functions, and the clinical sites, and any other activities for which outside expertise is required or desirable. The NIA project coordinator, who will also serve as the program administrator, will attend each meeting of this committee as an observer.

Genetic counseling and disease /care related information will be provided by the study for all of the participants in the study.

An important feature of this initiative is that the clinical, neuropsychological, imaging, and biological data and samples will be made available in the public domain to all qualified scientific investigators by methods and at time intervals to be determined by the Steering Committee.

It is not anticipated that clinical trials with biological or pharmacological agents would be conducted using funds from this award. However, this cohort of individuals from families with early onset dominantly inherited AD, which will initially be a valuable resource for clinical/neuropsychological, imaging, and biomarker studies, could also serve as a population from which to recruit in future clinical trials funded by other mechanisms.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U01 award mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The NIA intends to commit approximately $2,200,000 in direct costs, with total costs up to $3,000,000 dollars in FY 2008 to fund one application. The total project period for an application submitted in response to this funding opportunity may not exceed 6 years. The anticipated award date is not later than September 30, 2008.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

More than one PI, or multiple PIs, may be designated on the application. Additional information on the implementation plans and policies and procedures to formally allow more than one PI on individual research awards can be found at http://grants.nih.gov/grants/multi_pi. All PIs must be registered in the eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single PI or multiple PI grant is the responsibility of the applicant organization and should be determined by the scientific goals of the project. Applications for multiple PI grants will require additional information, as outlined in the instructions below, and the NIH review criteria for approach and investigator will be modified as indicated below. For example, a weak or inappropriate PI can have a negative effect on the review. If the multiple PIs grant option is elected, a contact PI must be named, as described in the instructions below. Multiple PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of all required reports.

2. Cost Sharing or Matching

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing

3. Other-Special Eligibility Criteria

Applicants may not submit more than one application for this initiative.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date(s): September 19, 2007
Application Receipt Date(s): October 19, 2007
Peer Review Date(s): January/February 2008
Council Review Date(s): May 2008
Earliest Anticipated Start Date(s): July 1, 2008

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Neil Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 350
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
Fax: (301) 496-1494
Email: buckholn@nia.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material (NIA encourages sending appendix materials on a CD rather than paper copies) must be sent to:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C212
7201 Wisconsin Avenue
Bethesda, MD 20892-9205 MSC 9205
Telephone: (301) 402-7702
Fax: (301) 402-0066
Email: NekolaM@mail.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will not be reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIA. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Background sections should be provided for the application as a whole (up to 10 pages). Following those sections separate sections should be prepared for the coordinating center (up to 15 pages), for the various cores/functions (up to 10 pages each), and for the clinical sites (3-4 pages/site). For the clinical sites summarize patient recruiting experience and potential for recruiting individuals with early onset dominantly inherited Alzheimer’s disease, neuropsychological and clinical experience with these individuals, experience as part of multi-site studies, MRI experience and scanner availability and access, and if applicable, PET experience and PET scanner availability and access.

Individual potential clinical sites may be included in more than one application.

Provide a flow chart or time line of the evaluations and procedures planned for subjects. Plans for ensuring compliance with HIPAA, data integrity, quality control, and data sharing should be discussed.

Personnel: For each of the components of the study, the application must describe the expertise of key scientific, technical and administrative personnel and include a mechanism for replacing key professional or technical personnel should the need arise.

Budget: The budgets should be based on the applicant's best judgment of activities likely to be involved during the different phases of the study as delineated under the section on Research Objectives including the number of subjects that are anticipated to be recruited and followed. Budgets should include costs of organizing at least two Steering Committee meetings annually and for attendance of necessary coordinating center, core/function, and clinical site staff, and other relevant individuals at these meetings. Budgets should include costs of at least one external scientific advisory committee meeting annually. Budgets should include projected data handling costs, reporting functions, meetings, and other communications costs. Clinical sites will be reimbursed for costs on a per visit/per protocol basis. Attempts should be made to utilize

existing clinical facilities, such as General Clinical Research Centers, Clinical and Translational Science Award institutions, and AD Centers. Only those research patient costs directly related to study activities may be charged to the study. Include an explanation of the programmatic, fiscal, and administrative arrangements made between the grantee administration and the collaborating institutions.

The coordinating center and the clinical sites should obtain IRB approvals consistent with the guidance on repositories from the NIH Office of Human Research Protections (OHRP):

http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm. The NIH brochure on research on human specimens may also be useful and can be found at: http://www.cdp.ims.nci.nih.gov/policy.html

Special requirements for this study are as follows:

1. The applicant should state the willingness and ability to cooperate with the cores/functions, the clinical sites, and NIA staff in all design, data collection, management, and distribution functions. The applicant should provide a plan for developing a cooperative relationship among the coordinating center, the cores/functions, the clinical sites and the other various organizational components.

2. A formal data-sharing plan must be included in the application, including a plan for a system that allows databases to be queried, in conjunction with coordinating center staff, by investigators not directly associated with the study. An essential feature of this study is that the clinical, neuropsychological, imaging, and biological data and samples will be placed in the public domain and made available to all qualified scientific investigators by methods and at time intervals to be determined by the Steering Committee.

3. Images should be centrally archived for centralized analysis for those comparisons that address the primary aims of the study. Data should be stored in the original and in any modified formats.

4. The applicant should indicate the willingness for using protocols that are consistent with the protocols developed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI; http://www.loni.ucla.edu/ADNI) for data and sample collection, storage, and analysis.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

An essential feature of this initiative is that the clinical, neuropsychological, imaging, and biological data and samples will be made available to all qualified scientific investigators by methods and at time intervals to be determined by the Steering Committee.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIA in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How will the development and implementation of this international network provide a clearer understanding of the clinical/neuropsychological, neuroimaging, genetic, and other biological aspects and underpinnings of the brain mechanisms involved in disease progression in these individuals with early onset dominantly inherited Alzheimer’s disease and how can this knowledge ultimately lead to better therapies? How will this network maximize the use of the data and samples collected as a resource to the scientific community?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Does the proposed approach in managing the

logistical aspects of coordination of the cores/functions and sites with the coordinating center have technical merit? Are the proposed plans and experience relating to subject recruitment and retention, staff training, data collection, monitoring, management, editing, processing, transfer, and reporting adequate? Is the approach to developing a cooperative relationship among the study sites and the various network

organizational components adequate? Are the plans for exercising appropriate leadership in matters of study design, data acquisition, data management, and data distribution demonstrated?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area? Are there novel ideas, hypotheses, and methods involving monitoring and predicting the progression of disease in individuals with early onset dominantly inherited Alzheimer’s disease using clinical/neuropsychological, neuroimaging, and biological data that will come from the development of this network?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Does the

application provide evidence of specific competence and relevant experience of professional, technical, and administrative staff pertinent to the operation of a coordinating center and cores/functions for multi-site studies? .

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? For the coordinating center, the cores/functions, and the clinical sites, does the scientific environment in which the work will be done contribute to the probability of success? Is there evidence of institutional support? Has the application documented the adequacy of the proposed facility, technical hardware, and space for the coordinating center, cores/functions, and clinical sites? Have the clinical sites had the necessary capabilities for the proposed neuroimaging studies including access to adequate time on the scanners? For clinical sites, is there a record of previous recruitment of these subjects and has the neuroimaging research experience been documented? Has evidence of institutional support and commitment been provided?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women and Minorities in Research: The adequacy of plans to include subjects from both genders and all racial and ethnic groups (and subgroups), as appropriate for the scientific goals of the research, will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

An essential feature of this initiative is that the clinical, neuropsychological, imaging, and biological data and samples will be placed in the public domain and made available to all qualified scientific investigators by methods and at time intervals to be determined by the Steering Committee.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible. However, reviewers will not factor the proposed research resource sharing plan into the determination of the scientific merit or priority score.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information

1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

2.A.1.Cooperative Agreement Mechanism

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees 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 award 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

This International Network for Identification, Evaluation, and Follow-up of Families with Early Onset Dominantly Inherited Alzheimer’s Disease consists of a coordinating center, a number of cores/functions, national and international clinical sites, and a Steering Committee.

2.A.2. Awardee Rights and Responsibilities

The awardee will have the primary responsibility for the overall management of the study through the coordinating center and should agree to work cooperatively with the cores/functions and clinical sites and will have the primary responsibility for developing and implementing systems necessary for communications among the various study organizational components. The coordinating center will facilitate the design and refinement of all protocols, manuals of operations, and forms.

The awardee institution will retain custody of, and primary rights to, the data developed under this award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies, with the added stipulation that all data and samples shall be placed in the public domain and shared freely by methods and within time periods to be specified by the Steering Committee, as a fundamental purpose of this study is the establishment of an unrestricted public database.

The primary governing body of the study will be the Steering Committee, which will have responsibility for the final details of study design and policy decisions and will define the rules regarding access to data and samples.

2.A.3 NIH Responsibilities

An NIH Project Collaborator will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

The designated NIA Project Collaborator will serve as a member of the Steering Committee and have substantial scientific/programmatic involvement during conduct of this cooperative agreement, through

technical assistance, advice, and coordination above and beyond normal program stewardship of grants. The awardee agrees to accept assistance from the designated NIA Project Collaborator. This person will participate, through the Steering Committee, in the monitoring of issues relating to recruitment, follow-up, QA/QC, and adherence to protocols and will assist in the development and/or adjustment of study protocols. The NIA Project Collaborator will also serve as the Program Official and will be responsible for the normal scientific and programmatic stewardship on this award and will be named in the award notice.

2.A.4. Collaborative Responsibilities

The Steering Committee, comprised of the PI of the cooperative agreement, the leaders of the cores/functions and each of the clinical sites, the bioethicist, the family representative, the FDA representative, and the NIA Project Collaborator will have primary responsibility for finalizing standard definitions, procedures, and measures common for all the protocols. The steering committee will meet every three to six months, or as dictated by the needs of the study. Each full member of the Steering Committee will have one vote, and all major scientific decisions will be determined by majority vote of the Steering Committee. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee. Subcommittees appointed by the Steering Committee, comprised of appropriate staff from the cores and clinical sites, will be involved in the design of protocols and manuals of operations, and in ongoing functions of the study such as preparation of publications.

To oversee the allocation and distribution of biological specimens generated from the study, the Steering Committee will nominate members for the Resource Allocation Review Committee (RARC). This group will review applications for use of the biological specimens. The format of the application and criteria for the use of repository biological specimens will be developed by the RARC with advice and approval from the Steering Committee and made available to all potential users. The RARC will be made up of individuals not directly involved in the study and without conflicts of interest. Membership on this committee will rotate periodically according to a procedure developed by the RARC. Final approval of members of the RARC and final approval for disposition of samples to investigators following RARC review will be made by NIA staff.

2.A.5. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: 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 awardee. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Neil Buckholtz, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building Number, Suite 350
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
Fax: (301) 496-1494
Email: buckholn@nia.nih.gov

2. Peer Review Contacts:

Mary Nekola, Ph.D.
Scientific Review Office
National Institute on Aging
Gateway Building Number, Suite 2C212
7201 Wisconsin Avenue
Bethesda , MD 20892-9205
Telephone: (301) 402-7702
Fax: (301) 402-0066
Email: NekolaM@mail.nih.gov

3. Financial or Grants Management Contacts:

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Street Address
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
Fax: (301) 402-3672
Email: whippl@nia.nih.gov

Section VIII. Other Information

Required Federal Citations

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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