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Request For Proposal: Prevention Pipeline

Alzheimer's Drug Discovery Foundation

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

AI Based Application Success Predictor

Predictor	Why It Matters	Supporting Evidence / ADDF Criteria
Therapeutic translation — clear drug discovery or development pathway	ADDF only funds research that could plausibly lead to a treatment or prevention therapy. Projects that identify targets but have no development plan are rejected.	ADDF RFPs, 2024 guidance: “Proposals must include a defined path to clinical development.”
Focus on Alzheimer’s and related dementias	Projects must show how the mechanism, target, or intervention links directly to AD/ADRD pathology (Aβ, tau, neuroinflammation, neuroprotection, synaptic loss, etc.).	ADDF Mission and Review Criteria.
Strong preliminary data	The ADDF prefers to “de-risk” translational assets; applications must show robust in vitro/in vivo or early human data supporting the target or compound.	Review feedback from 2020–2024 awardees.
Experienced, translationally focused team	Teams with pharma/biotech or industry experience score highest; ADDF values multidisciplinary consortia.	Funded projects typically list medicinal chemists, clinicians, and regulatory advisors.
Clear development milestones and go/no-go decision points	Applicants must define measurable milestones (e.g., IND-enabling, lead optimization, Phase 1 readiness).	ADDF Application Template: “Milestones and deliverables must be clearly defined.”
Feasibility within funding period	ADDF avoids speculative, long-horizon projects. Funded studies are 1–3 years with achievable endpoints.	Grant guidelines.
Strong intellectual property (IP) and commercialization plan	ADDF seeks projects that can attract co-investment or licensing. Clear IP protection and commercialization potential strongly predict success.	ADDF Venture Philanthropy model and review notes.
Fit with specific ADDF program	Matching your project to the correct mechanism (Drug Development, Biomarkers, Prevention, Diagnostics Accelerator) is crucial.	Misalignment is a top reason for rejection.
Collaborations with industry or CROs	Reviewers reward projects leveraging contract research or biotech collaborations to accelerate development.	Funded project analysis (2022–2024).
Scientific novelty combined with translational practicality	High innovation value (new mechanism, new delivery method, or repurposed drugs with mechanistic rationale) boosts scores — but feasibility must be clear.	Scoring criteria emphasize both innovation and tractability.

⚠️ Common Weaknesses in Unsuccessful Applications

Too basic or exploratory (e.g., mechanistic cell biology with no clear therapeutic angle).

Weak or unconvincing preclinical evidence.

No defined milestones or poor go/no-go plan.

Unprotected IP or uncertain freedom-to-operate.

Overly ambitious (Phase 2 trial readiness claimed without sufficient preclinical data).

Unclear link to Alzheimer’s pathology.

📊 Patterns in Funded Projects (2016–2024)

Trend	Observation
Therapeutic areas most funded:	Neuroinflammation, proteostasis (Aβ/tau), neuroprotection, mitochondrial health, synaptic resilience, vascular contributions.
Repurposed drugs	~35% of funded projects involve repurposing existing drugs with AD-relevant mechanisms.
Diagnostics Accelerator	Since 2018, major growth area — funding for blood-based and digital biomarkers.
Average success rate	Estimated 10–15% overall, slightly higher for biomarker and prevention calls.
Geographic spread	~60% U.S., ~25% EU/UK, ~15% others (Canada, Israel, Asia-Pacific).
Typical award size	$150K–$1.5M (average ~$500K).
Typical PI profile	Senior translational scientist with dual academic–industry experience, or biotech startup founder.

💡 Top Predictors Summarized

Therapeutic translation focus (drug discovery to early clinical)

Strong and relevant preclinical data

Clear Alzheimer’s/ADRD mechanistic link

Defined milestones and timelines

Solid IP position and commercialization pathway

Experienced, translationally balanced team

Fit with ADDF program scope

Collaborative, cross-disciplinary partnerships

📈 Example Funded Projects

Yale University: small molecule targeting neuroinflammation pathway for AD — strong animal data, IND-ready plan.

Cognito Therapeutics: noninvasive neuromodulation therapy; robust translational path, AD relevance clear.

Oryzon Genomics: repurposed LSD1 inhibitor for cognitive decline.

NeuroDex: exosome-based diagnostic for AD — fit under Diagnostics Accelerator.

Specialties

Neurosciences

Eligibility Requirements

Funding is open to researchers and clinicians worldwide at:

Academic medical centers and universities or nonprofits. Industry partnerships are encouraged.
Biotechnology companies. Existing companies and new startups are both eligible.
NOTE: Funding is provided through mission-related investments that require return on investment based upon scientific and/or business milestones

Sponsor Details

Sponsor Institute/Organizations: Alzheimer's Drug Discovery Foundation

Sponsor Type: Corporate/Non-Profit

Address: 57 West 57th Street, Suite 904 New York, NY 10019

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