Prevention

FUNDING OPPORTUNITY DESCRIPTION

The ADDF seeks to support precision prevention studies, combination therapy studies, and comparative effectiveness research that probe whether the use or choice of interventions may reduce the risk of Alzheimer’s disease or other dementias. Studies that are not in humans will not be considered.

Clinical Populations of Interest:

Primary Prevention: Primary Prevention studies include people without biomarker evidence of dementia pathology or dementia symptoms but who have specific risk factors for dementia. Relevant risk factors include: APOE4 genotype, hypertension, hyperlipidemia, type 2 diabetes mellitus, depression, obesity, hearing loss, vision loss, traumatic brain injury, postoperative delirium, postoperative cognitive dysfunction, menopause-related cognitive dysfunction, and others.
Secondary Prevention: Secondary Prevention studies include people with biomarker evidence of dementia pathology who do not yet have dementia symptoms. Biomarker evidence may include PET amyloid positivity, CSF biomarkers, or blood biomarkers indicating dementia pathology. Subjects may have specific risk factors for dementia, including APOE4 genotype, hypertension, hyperlipidemia, type 2 diabetes mellitus, depression, obesity, hearing loss, vision loss, traumatic brain injury, postoperative delirium, postoperative cognitive dysfunction, menopause-related cognitive dysfunction, and others.

The Prevention RFP Supports:

Precision Prevention and Risk Reduction: In July 2024, the Lancet Commission on Dementia Prevention, Intervention and Care reported that 45% of dementia cases may be prevented by fully addressing 14 modifiable risk factors. These modifiable risk factors include diabetes, hypertension, high LDL cholesterol, obesity, physical inactivity, depression, traumatic brain injury, hearing loss, vision loss, and others.

Dementia risk reduction through Precision Prevention can be achieved with a targeted, mechanism-specific preventative intervention in specific populations who are at risk for developing dementia due to these risk factors and/or genetic risk factors, such as APOE4, as well as other medical conditions linked to dementia risk, including postoperative delirium/cognitive decline, menopause-related cognitive symptoms, chemotherapy-induced decline, and long COVID-19.

The ADDF will consider funding programs that target and treat people with specific risk factors with the goal of modifying their dementia risk, as measured by outcomes related to dementia (e.g., cognitive function, neuroimaging outcomes, fluid biomarkers, and others). While interventions that are limited to lifestyle modifications alone (e.g., diet, exercise, etc.) will not be considered, studies combining a risk factor-targeted medication and/or supplement with lifestyle interventions can be considered (see “Combination Therapy Studies”).

Methods may include randomized controlled trials or epidemiologic studies. Long-term follow-up studies of successfully completed prevention clinical trials will also be considered. For clinical trial proposals, please see below detailed instructions and priorities under “Expectations and Evaluation.”
Combination Therapy Studies: Combination therapies are the standard of care for the treatment and prevention of many diseases of aging. While individual interventions may have only incremental benefits, the combination of two or more drugs targeting multiple risk factors or mechanisms related to the biology of aging may exert synergistic effects on outcomes related to dementia risk (e.g., cognitive function, neuroimaging outcomes, fluid biomarkers, and others). Randomized controlled studies testing a combination therapy of two or more agents (novel drugs, repurposed drugs, or supplements) or a combination product (containing two or more active substances within a single pharmaceutical or supplement form) will be considered. Studies combining a medication and/or supplement with lifestyle interventions will also be considered.
Comparative Effectiveness Research: For many medical conditions, physicians have a choice of prescribing clinically equivalent drugs. Some of these drugs are being investigated for repurposing to treat Alzheimer's or related dementias, due to potential disease-modifying properties that go beyond the treatment of their approved disease indication. The ADDF will consider funding research to test whether one or more clinically equivalent drugs of medical conditions is superior in protecting from Alzheimer’s disease or related dementias. Priority will be given to studies that fill a gap in literature and knowledge. Methods may include randomized controlled trials or epidemiology. For clinical trial proposals, please see below detailed instructions and priorities under “Expectations and Evaluation.” For epidemiological studies, those utilizing quality data from large sample sizes with detailed information on patient characteristics and relevant outcomes will be prioritized. Pooling or meta-analyzing data from multiple cohorts may also be appropriate, such as through leveraging the Cohorts for Alzheimer’s Prevention Action (CAPA).

Type of therapy: Novel, repurposed, and repositioned drugs, as well as natural products, supplements, and devices will be considered. The ADDF prioritizes studies of interventions with composition of matter intellectual property (IP), concrete strategies to develop novel IP, and/or a promising commercial path forward. Studies combining medications and/or supplements with lifestyle interventions will be considered. Lifestyle interventions (e.g., non-pharmacologic interventions, such as diet, meditation, and exercise) that are not combined with a study drug will not be considered.

Drug mechanisms or modes of action: Mechanisms and modes of action that target dementia risk reduction or biology of aging are considered high priority. These include, but are not limited to:

Metabolic and mitochondrial function
Vascular function
Inflammation
Neuroprotection
Epigenetics
Proteostatsis
Synaptic activity and neurotransmitters
Other mechanisms and modes of action related to the biology of aging (e.g. senescent cells)
Other novel mechanisms or modes of action that are supported by compelling evidence demonstrating a rational biological connection to dementia risk or onset
Please note: Anti-amyloid approaches (e.g., anti-amyloid aggregation, beta-amyloid vaccines, beta- or gamma-secretase inhibitors) and cholinesterase inhibitor proposals will not be considered

UPCOMING DEADLINES

ELIGIBILITY

AWARD INFORMATION

EXPECTATIONS AND EVALUATION

For clinical trial applications, the following guidance may assist you in developing a strong application that allows reviewers to better evaluate the science and merit of your proposal. The strongest proposals will contain many or all of the aspects listed below, although we recognize that the field is still in need of a better understanding of underlying biological mechanisms and validated biomarkers.

Please note: For clinical trial applications, the ADDF prioritizes novel drug candidates with composition of matter intellectual property (IP) and repurposed or repositioned drugs with concrete strategies to develop novel IP.

Mechanisms or modes of action: Applicants are encouraged to provide a clear rationale and compelling evidence for targeting the proposed mechanism or mode of action in the disease or condition and should specifically address these questions in the proposal:

How is the target biology more compelling than other related targets that have been tested?
Is there human genetic evidence linking the target biology to disease risk?
Is the target expressed in disease-relevant regions of the brain (or where applicable, in the periphery) in humans and/or animal models?
Are there changes in target mRNA/protein expression or activity in human disease specimens, and do they correlate with disease severity and cognitive functions?
Does genetic and/or pharmacological manipulation of the target in disease-relevant in vitro (e.g., primary cultured neurons/glia or cells derived from patient iPSCs) or in vivo models alter disease risk or phenotypes?
If the molecular target is unknown, the strength of the evidence for the mode of action and its link to disease pathophysiology will be evaluated. The applicant should summarize the existing evidence in the proposal.

Preliminary data: Applicants are encouraged to include data around many or all of the following:

Supportive preclinical efficacy data in relevant animal models
Evidence of blood-brain barrier penetration (for CNS targeted therapies)
Preclinical and, if available, clinical PK/PD data on dose optimization for the intended route of administration and dosing regimen
Preclinical and, if available, clinical data on biomarkers related to target engagement or mechanism of action
Preclinical and, if available, clinical safety data; proposals should include plans to address remaining safety concerns if any are identified in earlier studies

Clinical population: Proposals including patients should provide justification for the selected clinical population and how enrollment criteria, such as known genetics (e.g. ApoE status) and neuropathology (e.g. amyloid positivity), relate to the proposed mode of action. Applicants must provide information about recruitment of the target population to demonstrate that a sufficient number of patients are available to meet recruitment goals.

Expectations for Biomarker-Based Proof-of-Concept Studies:

Provide justification for the dose(s) selected.
Design studies to answer specific questions about a therapy’s activity, including whether an intervention is safe, engages its target, induces expected downstream pharmacological effects, and leads to changes on disease-related measures.
Include biomarker outcomes that align with the proposed mechanism or mode of action and, where possible, are predictive of clinical efficacy.
Include clinical assessments that align with the appropriate domains of the clinical syndrome and mechanism of action. Although these studies may not be powered to detect differences in clinical outcomes, the inclusion of cognitive and neuropsychological endpoints may be informative as exploratory outcomes. Expected directional changes that correlate with biomarker changes may be observed and can inform planning for subsequent studies.
Engage a biostatistician early in the development of the study design. Statisticians can help to determine the appropriate study design options and sample size calculations for these smaller biomarker-based studies, particularly when novel biomarkers without established effect sizes are used.

Investigative team: Clinical trials often require resources beyond those available at a single organization and collaboration with other investigators and contract research organizations and consultants are encouraged.

Please note: All clinical trials receiving ADDF funding must register and submit results for “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information website.

APPLICATION SUBMISSIONS

Review the Application Instructions for steps on applying.

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We encourage you to contact us if you would like to discuss your proposed project and receive initial feedback.

For inquiries, please contact:
ADDF Grants and Mission-Related Investments Team
grants@alzdiscovery.org

Alzheimer's Drug Discovery Foundation

A GuideStar-Rated Charity

57 West 57th Street, Suite 904
New York, NY 10019
info@alzdiscovery.org
212.901.8000