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:

Demonstrable innovation/novelty of the proposed project (especially in the context of the PI/PIs and team recent work). Priority will be given to projects that address an important knowledge gap in a way it is not being addressed through other funding mechanisms. Alignment with the research priorities of the RFA. Impact of project on AD research. Evidence of methodological rigor that address the research question(s) being proposed. 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.