Release Date:  December 6, 2000

RFA:  AG-01-003

National Institute on Aging
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  January 16, 2001
Application Receipt Date:       February 20, 2001



In July of 2000 it was announced that the NIH would set aside $50 
million over five years to support research on new ways to treat 
Alzheimer's disease, an ongoing commitment, by targeting the production 
of disease-associated processes, such as formation of amyloid plaques 
and neurofibrillary tangles with a special emphasis on the development 
of a vaccine to prevent the disease.  This RFA is intended to assist in 
the development of immunological preventive and treatment strategies 
for Alzheimer’s disease.  As part of the overall initiative, several 
related program announcements, with set-asides, are also being 

 It has been estimated that as many as four million Americans currently 
suffer from Alzheimer's disease, and failure to successfully prevent 
and treat the disease will result in more than a tripling of its 
prevalence - from four to fourteen million - over the next 50 years.  
Thus, the National Institute on Aging (NIA) and the National Institute 
of Neurological Disorders and Stroke (NINDS) invite applications for 
research project grants (R01) that will further the understanding of 
the biological, immunological and immunopathological bases for the 
prevention or successful removal from brain of the hallmark lesions 
seen in individuals with Alzheimer's disease.  These are beta amyloid 
(Abeta)-containing deposits of plaques in the extracellular space as well 
as tau-containing neurofibrillary tangles (NFT) within neurons.

Although the cause of the disease is still unknown, new research has 
shown that the prevention and treatment of Alzheimer's disease (AD) 
might be approached through the development of a vaccine targeted at 
preventing, delaying, or reversing the formation of AD-associated 
pathologic lesions.  These recent results, using a transgenic mouse 
model, have suggested that immunological interventions can retard and 
even reverse the development of at least some of the pathologic changes 
associated with AD.  Animal models of several autoimmune and 
inflammatory diseases (diabetes, experimental autoimmune 
encephalomyelitis and arthritis) have been successfully treated in this 
way.  Schenk et al. were the first to show that immunization with (Abeta)-
amyloid  prevented, and even reversed, plaque deposition in a 
transgenic mouse model of AD (Schenk et al., Nature 400:173-177, 1999).  
Since then, two additional studies in support of the findings have been 
published (Bard et al., Nature Medicine, 2000; Weiner et al., Annals of 
Neurology, 48: 567-579, 2000).  Presentations at the World Alzheimer 
Congress, 2000 and papers in Nature (in press) showed preliminary 
evidence that vaccination prevents the cognitive decline seen in other 
plaque-producing strains of transgenic mice (Janus et al., Neurobiology 
of Aging 21: S61(abstract no. 275), 2000; Morgan et al., Neurobiology 
of Aging 21: S18 (abstract no. 83), 2000).  Based on these data, there 
is a pressing need to understand the immunological processes involved 
that appear to limit the deposition of amyloid or enhance its removal 
from brain; to determine whether a similar approach may be useful for 
removal of NFT; and to determine which process, if any, prevents the 
related cognitive decline.


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 Request for 
is related to one or more of the priority areas.  Potential applicants 
may obtain a copy of "Healthy People 2010" at 


Applications may be submitted by domestic and foreign for-profit and 
non-profit organizations, public and private, such as universities, 
colleges, hospitals, laboratories, units of state and local 
governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.


This RFA will use the National Institutes of Health (NIH) individual 
research grant application (R01) mechanism.  The total project period 
for an application submitted in response to this RFA may not exceed 
five years.  Responsibility for the planning, direction, and execution 
of the proposed project will be solely that of the applicant or 
This RFA is a one-time solicitation, with an anticipated award date of 
September 15, 2001.  Future applications for the competing continuation 
of successful responses to this RFA will compete with all other 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures.

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being used by 
the NIH. Complete and detailed instructions and information on Modular 
Grant applications can be found at:


An estimated $4,500,000 will be available for the first year of support 
and a total of  $22,500,000 will be available over 5 years.  Between 10 
and 14 new awards will be made.  Direct costs will be awarded in 
modules of $25,000 up to $300,000.  Awards are contingent upon 
availability of funds and the receipt of a sufficient number of 
applications of outstanding scientific and technical merit.



Both early- and late-onset AD are neurodegenerative diseases marked by 
overproduction of (Abeta)-amyloid (Abeta) from amyloid precursor protein (APP) 
with subsequent deposition of (Abeta) into extracellular plaques in regions 
of brain responsible for memory and cognition.  In addition, there is a 
massive accumulation of abnormal tau filaments in NFT and considerable 
neuronal degeneration associated with a reactive gliosis (Praticò and 
Trojanowski, Neurobiology of Aging 21, 441-445, 2000). The deposition 
of amyloid appears to be a very early, perhaps the first, event in the 
pathogenesis of AD (Naslund et al., JAMA 283:1571-1577, 2000), 
preceding any cognitive impairment.  Its presence may modulate a number 
of biochemical pathways that result in the deposition of still other 
proteins, the activation of astroglia and microglia, and eventually 
neuronal cell death and consequent cognitive dysfunction.

Although inflammatory mediators such as interleukins and tumor necrosis 
factor are abundant in the brains of individuals with AD, AD pathology 
is unlike that seen in other diseases, such as multiple sclerosis, that 
are marked by the classical criteria of neuroinflammation (Raine, 
Neurobiology of Aging 21: 437-440, 2000).  It is unclear whether or not 
the upregulation and localization of inflammatory mediators in or near 
AD plaques are solely part of a vicious cycle contributing to 
progression of AD pathology or whether some components may be part of a 
protective or reparative response.  The recent evidence that an (Abeta)-
elicited immune response can virtually eliminate plaque development in 
a mouse model of AD suggests that an immunotherapeutic approach to the 
treatment of AD is a possibility.  Thus, the development of therapies 
for Alzheimer's disease that use a vaccine approach and research aimed 
at understanding the immunological bases for this approach are being 
solicited in this RFA.

Based upon the limited results available thus far in an animal model of 
AD or in an ex vivo assay of AD brain sections, the removal of 
(Abeta)/amyloid from brain in response to immunization against amyloid 
peptide has been achieved by circulating antibody, at least in part 
through induction of an Fc receptor-mediated uptake and clearance of 
the (Abeta) by activated microglia or CNS macrophages (Bard et al., Nature 
Medicine 6: 916-919, 2000; Walker, Journal of Neuroimmunology 94: 127-
133, 1999).  However, some role for cell-mediated immunity in this 
clearance process cannot be ruled out.  Understanding just how closely 
the (Abeta)-rich plaques or other AD pathologies that develop in animal 
models mirror the human condition, especially with respect to the 
presence of inflammatory modulators, is important because the closer 
the model, the better the results obtained can be translated to humans.  
For example, circulating, local and plaque-bound cytokines, chemokines, 
complement and complement inhibitors (Murphy et al., Amer. J. Path. 
157:895-904, 2000) have not been well studied in any of the models.  
For the development of truly effective AD vaccines, there is also a 
need to know more about the factors that control the activation and 
proliferation of the key cell types involved with the immune response 
to AD target antigens, and their effects on amyloid and NFT clearance 
as well as on brain and cognitive function.

Thus, the widespread amyloid deposition, activation of microglia and 
presence of NFT in AD might be amenable to a therapeutic vaccination 
stratagem that is designed to prevent the deposition of (Abeta) in plaques or 
tau in NFT in the first place or, once present, to rid the brain 
parenchyma of extracellular amyloid and intracellular NFT. In this way, 
there may be a role for both humoral and cell-mediated immune 
mechanisms in the prevention and treatment of AD.  Answers to the 
questions of exactly how the vaccine works are of paramount importance: 
The answers obtained through such studies will be of value both in the 
context of vaccine development and in providing further insight into 
the relationship between the immunological processes in brain and the 
etiology, pathogenesis, treatment and prevention of AD.  They may also 
shed light on age-related cognitive deficits.

Research Objectives and Approaches

o  It is anticipated that most applications submitted in response 
to this RFA would utilize animal model systems of AD.  Any one of 
a number of mouse transgenic (tg) models might be used (reviewed 
in Emilien et al., Arch Neurol 57: 176-181, 2000). Other mouse 
and animal models (for example rat, dog, guinea pig or miniature 
pig) also could be considered.  Animal models having a full range 
of AD pathology (plaques, tangles, neuritic dystrophy and cell 
death) and which also show cognitive decline would be the ideal.  
Applicants are encouraged to contact program staff concerning 
sources for in vivo models.  A well-justified rationale for 
whatever model is selected will be essential. Analyses using any 
of the models could be either in vivo, ex vivo, or in vitro.  
Studies involving living human subjects will be considered non-
responsive to this announcement.  However, studies that use human 
autopsy materials are allowed.

o  The most effective protocol for induction of an effective 
immune response, for example route of administration, schedule of 
immunization, and antigen dose, as well as the means by which 
immunogen is delivered and, where appropriate, the choice of 

o   The effect of  vaccination on the major outcome measures, 
including different behavioral tests of learning and memory that 
are both appropriate and adequate for a given cognitive domain

o   The minimal epitopes in a given antigen (e.g. (Abeta)-amyloid, tau, 
or other plaque constituents) to elicit cell-mediated or humoral 

o   The potential role of cell-mediated immunity in protection 
from AD pathology

o   Identification of subtype and time course of humoral or cell-
mediated effects 

o   The immune-mediated mechanisms that account for inhibiting 
plaque deposition or facilitating its removal

o   The effect of age-related changes in the functional 
competency and constitution of the immune system, with particular 
emphasis on factors relevant to human subjects

o   In addition to protein antibodies, the development and use of 
novel immuno-therapeutics, for example DNA and RNA vaccines and 
bifunctional chimeric antibodies

o   Monitoring the removal of plaques or NFT and/or their 
constituents by in vivo imaging, brain PET tracers, 
CSF/serum/plasma/urine ELISAs, or mass spectrometry measures

o   Localization and extent of immune activation response in 
different brain regions, and its effects

o   The possible induction of tolerance in response to repeated 

o   The possible development of sensitization and autoimmune 
disease with non-specific effects in organ systems and other cell 

o   Interference with the normal function of APP or amyloid 
precursor-like proteins or tau

o   Possible negative effects of immunization and development of 
an immune response in brain

o   Effects on other tissues and intracellular pathways


All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, Internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.


Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the 
identities of other key personnel and participating institutions, and 
the number and title of the RFA in response to which the application 
may be submitted. 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 to plan the review.

The letter of intent is to be sent to the program staff listed under 
INQUIRIES by the letter of intent receipt date listed in the heading of 
this RFA.


The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.  
These forms are available at most institutional offices of sponsored 
research; from the Division of Extramural Outreach and Information 
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 
7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:; and on the internet at:

The RFA label available in the PHS 398 (rev. 4/98) application form 
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 sample RFA label available at: has been 
modified to allow for this change.  Please note that this sample label 
is in pdf format.

The modular grant concept establishes specific modules in which direct 
costs may be requested as well as a maximum level for requested 
budgets. Only limited budgetary information is required under this 
approach. The just-in-time concept allows applicants to submit certain 
information only when there is a possibility for an award. It is 
anticipated that these changes will reduce the administrative burden 
for the applicants, reviewers and Institute staff. The research grant 
application form PHS 398 (rev. 4/98) is to be used in applying for 
these grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 
modules. The total direct costs must be requested in accordance with 
the program guidelines and the modifications made to the standard PHS 
398 application instructions described below:

PHS 398

o   FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to $300,000) in the initial budget 
period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

Form Page 4 of the PHS 398.  It is not required and will not be 
accepted with the application.

the categorical budget table on Form Page 5 of the PHS 398.  It is not 
required and will not be accepted with the application.

o   NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See for sample 
pages.)  At the top of the page, enter the total direct costs requested 
for each year. This is not a Form page.

o   Under Personnel, list all project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided. However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000.  List the individuals and organizations with 
whom consortium or contractual arrangements have been made, the percent 
effort of all personnel, and the role on the project.  Indicate whether 
the collaborating institution is foreign or domestic.  The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount.  Include the Letter of Intent to 
establish a consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

o   BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's qualifications 
for a specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team.  A biographical sketch is 
required for all key personnel, following the instructions below. No 
more than three pages may be used for each person.  A sample 
biographical sketch may be viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST - This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate 
the type of agreement and the date. All appropriate exclusions must be 
applied in the calculation of the F&A costs for the initial budget 
period and all future budget years.

o   The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.  

Submit a signed, original of the application and three signed, 
photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, send two additional copies of the 
application to:

Mary Nekola, Ph.D.
Chief, Scientific Review
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212
Bethesda, MD  20892-9205

It is important to send these copies at the same time as the original 
and three copies are sent to the Center for Scientific Review. These 
copies are used to identify conflicts and to help ensure the 
appropriate and timely review of the application.

Applications must be received by the application receipt date listed in 
the heading of this RFA.  If an application is received after that 
date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an introduction addressing 
the previous critique.


Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by NIA and NINDS staff. Incomplete applications will be 
returned to the applicant. If the application is not responsive to the 
RFA, CSR staff may contact the applicant to determine whether to return 
the application to the applicant or submit it for review in competition 
with unsolicited applications at the next review cycle.

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, a process may be 
used by the initial review group in which applications receive a 
written critique and undergo a process in which only those applications 
deemed to have the highest scientific merit, generally the top half of 
the applications under review, will be discussed, assigned a priority 
score, and receive a second level review by the National Advisory 
Council on Aging and the National Advisory Neurological Disorders and 
Stroke Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments reviewers will be asked to discuss the 
following aspects of the application 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 the 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.

1.  Significance:  Does this study address an important problem?  If 
the aims of the application are achieved, how will scientific knowledge 
be advanced?  What will be the effect of these studies on the concepts 
or methods that drive this field?

2.  Approach:  Are the conceptual framework, design, methods, and 
analyses adequately developed, well-integrated, and appropriate to the 
aims of the project?  Does the applicant acknowledge potential problem 
areas and consider alternative tactics?

3.  Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 

4.  Investigator:  Is the investigator 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 
(if any)?

5.  Environment:  Does the scientific environment in which the work 
will be done contribute to the probability of success?  Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support?  The adequacy of the proposed 
protection for animals or the environment, to the extent they may be 
adversely affected by the project proposed in the application should be 

The personnel category will be reviewed for appropriate staffing based 
on the requested percent effort.  The direct costs budget request will 
be reviewed for consistency with the proposed methods and specific 
aims.  Any budgetary adjustments recommended by the reviewers will be 
in $25,000 modules.  The duration of support will be reviewed to 
determine if it is appropriate to ensure successful completion of the 
requested scope of the project.


Letter of Intent Receipt Date:  01/16/2001
Application Receipt Date:       02/20/2001
Date of Initial Review:         05/07/2001
Review by Advisory Council:     08/25/2001
Anticipated Award Date:         09/15/2001


Award Criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities


Inquiries concerning this RFA are encouraged.  Additional information, 
including sample budget narratives and biographical sketch, may be 
found at this site:  The 
opportunity to clarify any issues or questions from potential 
applicants is welcome.

Direct inquiries regarding programmatic issues to:

D. Stephen Snyder, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494

Diane D. Murphy, Ph.D.
Program Director
Neurodegeneration Program
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2223
6001 Executive Boulevard
Bethesda, MD 20892-9525
Telephone: 301/496-5680
FAX: 301/480-1080

Direct inquiries regarding fiscal matters to:

Ms. Linda Whipp
Acting Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672

Kimberly Pendleton
Grants Management Specialist
Grants Management Branch, DEA
Neuroscience Center, Room 3254
6001 Executive Boulevard
Bethesda, MD 20892-9525
Telephone: (301) 496-9231
FAX: 301-402-0219


The NIA and NINDS programs are described in the Catalog of Federal 
Domestic Assistance Nos. 93.866 and 93.853. Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and administered under NIH grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  
This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-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 

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