APOE Biology in Alzheimer’s (ABA) - Implications for Biological Underpinnings, Risk, Progression and Outcomes

 

Program objective

The Alzheimer’s Association, in collaboration with the WoodNext Foundation, aims to support innovative, high-risk, collaborative team science opportunities that investigate and focus on outstanding questions related to the biological underpinnings of Alzheimer’s disease (AD). This funding call will focus on projects aimed to advance our understanding of the role of APOE in genetically diverse populations. Projects should address scientific questions that better understand the impact of this gene and its product on biological underpinnings, risk, progression and individual outcomes. This program aims to incentivize research focused on APOE related questions that would not happen otherwise, targeting unmet needs in the APOE space that are not being addressed through other funding mechanisms.

This funding call builds off past investments by the Association, through the Alzheimer’s disease Strategic Fund (ADSF), which was established in 2019 to support studies that advance our understanding of Alzheimer’s, including the role of APOE.

Program overview

Although Alzheimer’s research has made many advances in recent years, the field still faces gaps in our knowledge and ability to translate basic science discoveries into effective treatments and evidence-based clinical practices for dementia care. Some of these overarching questions focus on understanding of disease causes, need for models and other tools to evaluate disease biology, early and accurate detection and diagnosis procedures and diverse treatment modalities.

Variants in the APOE gene, which is the major cholesterol carrier in the brain, are a significant risk factor for AD in some populations. Although the risk due to APOE in some populations has been known for decades, the Alzheimer’s research community does not fully understand how differences in the APOE gene confer risk of AD.

Advances in tools and technology are now allowing research teams to probe the role of APOE in a much more sophisticated way, and scientists are beginning to develop new hypotheses for the way APOE contributes to disease. Technologies have evolved and are now able to increase or decrease levels of specific forms of APOE; however, the use of these technologies requires a greater understanding of the biological underpinnings to deploy these potential therapeutics. While aadditional understanding of this target could enable timely clinical trials, human trial studies and/or any cohort studies that propose to add APOE related genotyping in the absence of scientific discovery or analysis are considered outside the scope of this funding program.

The APOE Biology in Alzheimer’s (ABA) Grant Program 2024 solicits projects that aim to address some of the key challenges in Alzheimer’s research today as related to APOE contributions and biology, including but not limited to:

• Cause(s) of the Disease: What are the biological mechanisms by which APOE genotype is altering overall risk for AD? For example, how is APOE contributing to the following basic questions of AD pathophysiology: How and why do specific sets of neurons in select brain structures become dysfunctional in disease? Why is there selective vulnerability in specific brain regions and not in others? What initiates these processed and are they cell autonomous or non-cell autonomous in nature? How do other identified risk/resilience genes interact with APOE-related biology? This could include projects aimed to address the biological significance of APOE to risk and resilience in different populations, including impact on risk and mutations, impact on resilience, and links to cardiovascular/ cerebrovascular related pathways or metabolic disorders, or studies aimed to understand the biological role of APOE as relates to transport metabolism. Importantly, how genetic ancestry influences the contribution of APOE genotype to disease, and an understanding of the underlying biology that this altered risk is of particular interest.
• Early and Accurate Detection and Diagnosis: How might APOE genotype affect specific biomarkers of disease? Projects may include work aimed to develop novel biomarkers and/or drug discovery and development (pre-IND) related to APOE to advance understanding of biological implications and contributions of APOE and related measures
• Treatment: Should therapeutic development be specifically targeted towards different APOE genotypes or specific trial designs? How might APOE impact a patient's specific response to a treatment? We would be interested in proposals that would provide support to help inform these types of decisions.
• Tool development: What are key tools and/or resources that if developed will benefit a broader range of scientific questions and/or studies related to APOE biology? Tools and resources developed through this funding would be made broadly available to the scientific field. This could include the development of Experimental Models of Disease. Considerable advances have been made in the development of cellular and animal models for AD that incorporate APOE contributions and APOE-related genes; however, these model systems do not capture the full complexity of the human condition. This has been problematic in applying these models to predict the success of specific therapeutic interventions in individuals with AD. Are there novel technologies or approaches that recapitulate disease progression and/or pathogenesis to support model applications that will particularly help to address the role of APOE?

The ABA 2024 Grant Program aims to fund concerted and collaborative efforts that will explore these questions as they relate to APOE to advance our understanding of disease.

Funding and award period

The maximum grant amount is $300,000; with anticipated funding ranges to be $150,000 to $300,000 depending on the project scope. Budget spending should be appropriately aligned to the specific aims and proposed milestones of the project. No indirect costs are allowable for this funding program. The maximum project duration is 3 years, and there is no minimum timeframe. The Association will evaluate projects on progress toward specific milestones; continued disbursement of funds is dependent on demonstrated progress toward key milestones.

Eligibility

The ABA Grant Program is open to researchers at academic institutions and other non-profit research institutions. The Principal Investigator of the project must be a full-time faculty member or paid employee of the organization submitting the proposal. If the applicant is not a paid employee, they must demonstrate that they are part of the instituation and a listed employee. Applications from post-doctoral researchers will not be accepted.

Investigators that have received Alzheimer’s Association funding and are currently delinquent in submitting required reports or have awards closed as “Incomplete” are not eligible to apply. For questions about eligibility, please contact the Alzheimer’s Association at grantsapp@alz.org.

Note: Alzheimer’s Association grants are generally open to scientists and researchers across the globe; however, as a U.S.-based charity, the Alzheimer’s Association is subject to, and complies with, U.S. law. As a result, the Alzheimer’s Association cannot award, and will not award, grants in violation of applicable U.S. statutes and regulations. This means, among other things, that the Alzheimer’s Association cannot, and will not, fund any individual or entity (i) that s subject to U.S. comprehensive or targeted sanctions or if awarding funding would result in a violation of such sanctions, (ii) that is on the U.S. List of Specially Designated Nationals or entities owned or controlled by such persons, or (iii) when doing so is otherwise prohibited by U.S. laws related to combating terrorism.

Submitting a Letter of Intent

The Letter of Intent (LOI) is a required step in the application process. LOIs must be completed online at https://proposalcentral.com. First-time users must register and complete a Professional Profile to begin the LOI process. No hard copies will be accepted. The LOI is completed through the online interactive system; you will need to complete the required sections and upload any required documents. The main section will have a limit of 10,000 characters, approximately 3 pages, and should include the information below (no figures/graphics or images are allowed):

• Brief project description, including methodology
• Specific aims of the project
• Innovation/novelty of the project
• Project team
• Plan for data management and data sharing

For U.S. entities, the LOI materials will include proof of your organization’s not-for-profit status and a W9 signed and dated by the signing official. Non-US entities must provide a W8-BEN-E signed and dated by the signing official. Your LOI will not be accepted without these documents. Current awardees of Alzheimer’s Association are eligible provided current funded grant does not overlap with this proposal. 
 

Evaluation of LOIs

Only LOIs that meet program specific guidelines and meet review criteria, including the goals of the ABA 2024 program, will be invited to submit full applications. LOIs will be reviewed by a panel of experts with special attention to:
 

1. Demonstrable innovation/novelty of the proposed project (especially in the context of the PI/PIs and team recent work).
2. Priority will be given to projects that address an important knowledge gap in a way it is not being addressed through other funding mechanisms.
3. Alignment with the research priorities of the RFA.
4. Impact of project on AD research.
5. Evidence of methodological rigor that address the research question(s) being proposed.
6. Priority will be given to studies that leverage and/or identify new opportunities for team science, collaborations and working across disciplines that otherwise could or would not happen.

Feedback is not provided for LOIs that are not invited to submit a full application.
 

Submitting a full application

For those invited to submit a full application, additional materials will be required. Templates and instructions will be provided after LOI approval.

Full applications will include:
 

• Executive Summary (1 page).
• Background/ Rationale (1 page): should include background and clearly defined hypothesis and/or rationale addressing why strategy is expected to be fruitful. This should also note the specific aims.
• Work Plan (up to 5 pages): should include goals/specific aims, methods and project plan and should be organized in alignment with the milestones as outlined in the application.
• Project Milestones: workplan should be separated into one-year intervals with specific milestones to be accomplished within that timeframe. Milestones should align with the overall project goals and be designed for easy progress evaluation and for clear determination on whether or not milestones have been met. For each milestone, indicate the relevant Project Aim. (No upload required)
• Principal Investigator(s) and Key Personnel Curriculum Vitae or Biosketch (no more than 5 pages per person); there is no limit on the number of CVs to be included.
• Available Resources and Budget Justification (2 pages):
  • Expenses that will not be allowed under this award include: tuition for full degree programs, rent for laboratory/office space, construction or renovation costs, liability insurance, networking and communication fees, and any facilities fees and laboratory/supply costs not directly relevant to the project. If awarded, a full budget of planned expenses will be required.
  • Include a list of tools/models available (if appropriate, list critical tools and models to be used or needed in the course of the research). No indirect costs will be allowed. Budget should be broken down in 1-year increments and align with project milestones.
• Data Management and Sharing Plan (3 pages): we recommend using the provided amended NIH template. It is expected that data generated through this funding mechanism will include a robust plan for sharing data and an appropriate included budget to accommodate this plan. Data sharing is a key component of the application and will be considered in the review and evaluation. Information on timelines, feasibility, and the platform(s) and/or mechanisms of sharing should be included. Failure to share data appropriately may prevent investigators from being eligible for future funding. When data sharing may be limited, applicants must explain such limitations at the time of application.
• Recruitment Plan (1 page): Only for projects using human research participants.
• Citations/References (1 page): Use the reference style that is most common in the major journal(s).
• Up to 3 letters of support (no more than 2 pages each) are allowed.
• W9/W8 Documentation.

Evaluation of full applications

Full Applications will be reviewed by a panel of experts with special attention to:
 

1. Alignment with the research priorities of the RFA.
2. Demonstrable innovation/novelty of the proposed project (especially in the context of the PI/PIs’ and team’s recent work); innovation could include scientific areas not well-understood, leveraging unique technologies or model systems to approach APOE-related mechanisms, bridging disciplines to understand the intersectionality of thebiological underpinnings. 
3. Priority will be given to projects that address an important knowledge gap in a way it is not being addressed through other funding mechanisms; applications should provide context for what is and is not known in the area of research being proposed.
4. Evidence of methodological rigor that addresses the research question(s) being proposed, including the power necessary to sufficiently address the question proposed.
5. Priority will be given to studies that leverage and/or identify new opportunities for team science, collaborations and working across disciplines that otherwise would not happen
6. Quality and Adequacy of Resources and Budget.
7. Potential Iimpact of the project on AD/ADRD research.

Deadlines and award timeline

Key Dates for this program include:
 

• Letter of Intent Launch - Early July 2024 on proposalcentral.com
• Letter of Intent Deadline - August 19, 2024 at 5 p.m. ET (no exceptions)
• Application Deadline - October 15, 2024 at 5 p.m. ET (no exceptions)
• Application Review - Throughout mid-October thru mid-December 2024
• Award Notifications - By December 16, 2024

LOIs will be accepted through 5 p.m. ET, August 19, 2024. Letters of Intent will not be accepted after this date. No exceptions will be made.
 
All LOIs must be completed online at proposalcentral.com. No hard copies or emails will be accepted.   
 
For those invited to submit a full application, the full application must be received by 5 p.m.. ET, October 15, 2024. Applications will not be accepted after this date. No exceptions will be made. No hard copies or emails will be accepted.
 
Award announcements will be made by December 16, 2024.

For more information, contact grantsapp@alz.org.

Additional details 

It is the responsibility of the applicant to ensure and verify that:
 

• The application is submitted by the receipt date/time deadline. Once submitted, you will receive a confirmation email from proposalcentral.com that your application was successfully submitted. If you do not receive a confirmation, click the Proposals tab and under the “Status” column, make sure it says Submitted and not In Progress, which indicates you have not yet submitted your application.
• The application is complete and accurate before submission. Only a single copy of an application will be accepted. We do not require signatures at the time of submission. The signature page provided is for use should your institution/organization require signatures; we do not override any institutional policies and/or procedures. Please do not submit the signature page with your application.
• Revisions, additional materials, and/or reference, manuscripts, appendices, etc., are not allowed and, if attached, will be removed from your application. Up to 3 letters of support (no more than 2 pages each) are allowed. Additional letters will be removed. 

Multiple and overlapping submissions

Multiple submissions from one applicant is not permitted. This includes multiple submissions from the same group and/or collaborators.
 

Allowable costs under this award include: 

• Purchase and care of laboratory animals.
• Small pieces of laboratory equipment and laboratory supplies (purchases over $10,000 require prior approval, even if included in the project proposal budget). 
• Computer software - if used strictly for data collection and/or analysis.
• Salary for the principal investigator, scientific (including postdoctoral fellows) and technical staff (including modest administrative support).
• Research supplies needed for the proposed studies.
• Support for travel to scientific and professional meetings and additional support for travel expenses necessary to carry out research planned– this may include site visits. A total of $12,500 over a three-year period may be requested for travel purposes and is not to exceed $7,000 in any given year.
• Open access publications fees are appropriate and reasonable for the project budget.

Not allowable as direct costs under this award include:

• Computer hardware or standard software (e.g., Microsoft Office).
• Construction or renovation costs.
• Tuition for students or for educational training for trainees or faculty.
• Service contract fees for equipment.
• Construction or renovation costs.
• Tuition.
• Rent for laboratory/office space.
• Visa costs and fees.
• Expenses such as Data Network Recharges and Computing and communication device support services. However, data sharing and/or data storage for imaging, sequencing, and other study data is allowed.
• General liability insurance, such as GAEL.
• Wire and currency exchange fees.
• The Alzheimer’s Association Medical and Scientific Advisory Group (MSAG), the International Research Grant Program (IRGP) Council members, and current employees of the Alzheimer’s Association are allowed to be key personnel or collaborators on projects, however they are NOT ALLOWED to receive any salary or compensation. A complete list of MSAG and IRGP Council members can be found on our website alz.org/grants.
• No indirect costs are allowed.

Additional information

 

Ethical/regulatory approvals and reporting requirements

If awarded for funding, the Alzheimer’s Association require that any necessary ethical and/or regulatory approvals are kept current, and may require specific reporting throughout the lifetime of the award. This includes, but is not limited to, the following:
 

Human subject assurances

Human subject assurances are not required at the time of application. Investigators have up to 90 days after receipt of their award notification to submit these documents. However, the Alzheimer’s Association encourages investigators to initiate their certification applications on a schedule that recognizes that approvals at many institutions can take more than 90 days. We will accept only certifications that apply specifically to the funded project and must include the name of the awardee. An award letter will not be issued unless the appropriate certifications are in place and include the name of the awardee within the 90 days from award notification. The same applies for animal ethical approvals, if applicable. 
 

Annual scientific and financial reports

Interim Scientific and Financial Reports must be submitted at the end of each reporting period as long as the grant remains active. Final Scientific and Financial Reports must be filed within 90 days of the grant‘s end date. All reports must be submitted electronically via proposalcentral.com. The Financial Report must be approved and signed by someone with financial authority in the Office of Research and Sponsored Programs at the recipient‘s institution.
 

Data sharing

The Alzheimer’s Association requires the timely release and the sharing of final research data and other research resources generated from Alzheimer’s Association funded research studies be shared and administered in accordance with this policy. Examples included in the “final research data” are the data, samples, physical conditions and other supporting materialscreated or gathered during the course of the work. The following principles should be followed:
 

• Share data, tools, and results within the consortia in near real time;
• Make useful datasets and supporting information available to the broader research community every 12 months, at minimum, through an appropriate data-sharing platform and other repositories, noting that not all experimental datasets are useful at early or intermediate stages of generation, exceptions may be made on a case-by-case basis if the AD Strategic Fund agrees that the data are not yet ready to be shared.
• Use a streamlined data access process for the data sharing platform to allow high throughput management of data access request approvals; make novel tools and research reagents (including, but not limited to, research models, cell lines, plasmids, viral vectors, antibodies, code/analysis methods, etc.) available as quickly as possible to academic and industry researchers either directly, or preferably through an appropriate and accessible distribution platform (e.g. Jackson Laboratory, Addgene, and GitHub) with minimal costs and restrictions.
• Whenever possible, avoid use of reagents, tools, samples, or data that cannot be easily shared; pre-approval for use of animal models that cannot be freely shared is required.
• Rapidly bring research findings and results to the research community through presentations at meetings and open-access publication (e.g. preprint servers, open access journals, or making papers available on the investigator’s website).

The teams’ commitment and expectations for sharing in a timely manner will be discussed and evaluated during the regular consortium teleconferences and meetings throughout the duration of the project. All project reports should include activities related to the sharing of their findings.
 

Recruitment efforts for clinical studies and/or studies that involve human materials

Projects involving human participants — whether directly recruiting or using materials from previously conducted studies — must address the appropriate inclusion or exclusion of individuals in the proposed research project. This is particularly important for work related to APOE given the emerging data around the genetic ancestry contribution.  

Financial responsibility

Funding is awarded to the institution and/or organization, not to the individual principal investigator. The principal investigator or a first-degree relative cannot be listed as the signing official or financial officer, or have checks sent to their attention if awarded.
 

Appeals of scientific peer review

To maintain a fair and rigorous review system, the Alzheimer’s Association have a process for appeal of funding decisions. Appeals will be not be considered for the letter of intent stage. Regarding applications, an appeal is intended to address extraordinary circumstances. Appropriate reasons for initiating an appeal might include:
 

• Evidence that a reviewer has an undeclared conflict of interest.
• An egregious error or misunderstanding in the review process.
• Active malfeasance or demonstrable lack of due diligence.

The appeal process is not intended to provide a mechanism for routine protest of failure to receive a grant. It is anticipated that funding through ABA Grant Program will be extremely competitive and is limited by availability of funds.
 
If an applicant believes an extraordinary circumstance has contributed to failure to receive funding, the principal investigator may send a two-page, double-spaced formal letter of appeal (Word document) to grantsappeals@alz.org. Any supporting documents included must be submitted as a PDF. Appeals must be submitted within 2 weeks from the date your application outcome notification is sent. Notification of action on the appeal will be made via email, usually within 90 days of the appeal deadline.

Nondiscrimination and harassment statement

Alzheimer’s Association is committed to providing an environment free from harassment and discrimination. Alzheimer’s Association strictly prohibits harassment and discrimination based on race; creed; color; religion; sex; sexual orientation; national origin; ancestry; age; Veteran status; citizenship status; marital status; physical or mental disabilities; pregnancy, gender identity or expression (including transgender status); genetic information; and any other characteristic protected by federal, state or local law.