Include Project: Vital Breakthroughs 2025

A Congressional Mandate for Down Syndrome Research

For decades, Down syndrome research was a quiet corner of the medical world, chronically underfunded and often overlooked. Individuals with Down syndrome and their families faced a healthcare system that reacted to problems rather than proactively managing them, armed with limited scientific understanding of the condition’s complexities. This landscape changed dramatically in 2018, not by slow evolution, but by a powerful Congressional directive that gave rise to the Include Project—formally the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project. This major NIH research initiative, launched in June 2018, represented a paradigm shift.

What it is:

• A trans-NIH research project focused on Down syndrome and its frequently co-occurring health conditions. The “trans-NIH” designation is critical, as it marshals the resources and expertise of nearly all NIH institutes and centers, many of which had never focused on Down syndrome before.
• Launched with an initial $23 million in dedicated funding for Fiscal Year 2018, its budget has grown exponentially, reaching an impressive $133 million by 2024.
• A comprehensive strategic framework built around three core, interconnected pillars: high-impact basic science, large-scale cohort building, and inclusive clinical trials.

Key Goals:

• To conduct rigorous scientific investigation into the health conditions, both common and rare, that affect individuals with Down syndrome throughout their lives.
• To dramatically improve health outcomes, quality of life, and longevity for every person with trisomy 21.
• To leverage the unique biology of chromosome 21 to generate discoveries that benefit broader populations, particularly in areas like Alzheimer’s disease, cancer, and autoimmune disorders.

Main Components:

• High-risk, high-reward basic science studies exploring the fundamental molecular and cellular consequences of having an extra copy of chromosome 21.
• The assembly of a large-scale, longitudinal cohort to track health and development over the entire lifespan, creating an unprecedented data resource.
• The establishment of inclusive clinical trials designed to test new treatments and interventions, ensuring the Down syndrome community is no longer excluded from medical advances.

The Include Project fundamentally altered the research ecosystem. After nearly two decades of being one of the least funded genetic conditions at the NIH, funding for Down syndrome research surged from just $18 million in 2009 to $133 million in 2024. This massive investment is a direct result of a Congressional mandate fueled by powerful advocacy, culminating in legislative efforts like the DeOndra Dixon INCLUDE Project Act.

The initiative’s strength lies in its collaborative nature, uniting multiple NIH institutes to tackle shared health challenges. By focusing on co-occurring conditions, the project ensures that findings will have a dual benefit: providing urgently needed answers for the Down syndrome community while simultaneously advancing knowledge for anyone affected by related conditions like Alzheimer’s disease, certain cancers, and autoimmune disorders.

As Dr. Maria Chatzou Dunford, CEO of Lifebit, I’ve dedicated over 15 years to developing the genomics and data platforms that power large-scale research. My experience in building secure, federated environments for sensitive health data is directly aligned with the collaborative infrastructure that makes ambitious initiatives like the Include Project not just possible, but successful.

Include Project terms explained:

• Cancer Moonshot
• Defense Health Agency

The Strategic Framework of the NIH INCLUDE Project

The 2018 Congressional directive demanded a radical transformation in Down syndrome research. The Include Project delivered with a comprehensive strategy built on three interconnected pillars. This unified approach shatters traditional research silos, creating a seamless pipeline that accelerates progress from the laboratory bench to the patient’s bedside. By tackling the issue from every angle—fundamental biology, large-scale population data, and real-world clinical trials—the project ensures that no stone is left unturned.

Pillar 1: High-Impact Basic Science Research

This pillar addresses the most fundamental question: what are the precise biological consequences of having a third copy of chromosome 21? This extra chromosome, containing over 200 genes, doesn’t just add a little extra genetic material; it creates a complex cascade of effects throughout the body. Researchers are meticulously studying gene expression patterns, discovering that the over-expression of genes on chromosome 21 leads to widespread gene dysregulation across the entire genome. This disruption of the cell’s delicate regulatory balance is believed to underlie many of the complex health features of Down syndrome. Key genes of interest include DYRK1A, which is involved in brain development and function, and RCAN1, which plays a role in cellular stress responses.

Breakthroughs in cellular models are providing powerful new tools. In one groundbreaking experiment, scientists used a molecule called XIST (X-inactive specific transcript), which is naturally responsible for silencing one of the two X chromosomes in females, to “turn off” the extra chromosome 21 in neural stem cells derived from individuals with Down syndrome. Remarkably, this genetic correction prompted the cells to develop into healthy, functioning neurons, offering a proof-of-concept for future genetic therapies.

Mouse models, such as the widely used Ts65Dn mouse, remain invaluable for studying developmental processes and testing potential treatments in a living organism. These models replicate many features of Down syndrome, allowing researchers to track disease progression and evaluate interventions. For example, studies in mice have shown that maternal choline supplementation during pregnancy can improve learning and memory in offspring with Down syndrome-like characteristics, a finding that has spurred clinical investigation in humans. Other research has revealed that supportive brain cells called astrocytes can become dysfunctional in Down syndrome, producing more harmful reactive oxygen species and fewer neuroprotective factors, contributing to neuroinflammation and cognitive challenges.

This foundational science is crucial for identifying new therapeutic targets. For instance, the discovery that three copies of the Amyloid Precursor Protein (APP) gene are a primary driver of Alzheimer’s disease in Down syndrome has led to research focused on modulating enzymes like BACE1 to reduce amyloid production, potentially preventing or slowing the disease’s onset.

Pillar 2: Assembling a Lifespan Cohort

Before the Include Project, Down syndrome research was often fragmented, consisting of small, short-term studies that provided only a snapshot in time. This pillar aims to create a complete motion picture: a comprehensive longitudinal study that follows thousands of individuals with Down syndrome throughout their entire lives. This “lifespan cohort” is the backbone of the project’s clinical research efforts.

The project is building this living dataset by connecting existing research groups, harmonizing their data, and recruiting new participants. This creates a powerful, unified network of information far greater than the sum of its parts. The data collected is extensive, including detailed medical histories, biosamples (blood, saliva for DNA and other analyses), neuroimaging scans, cognitive assessments, and behavioral questionnaires. The sheer scope of this cohort allows researchers to track how conditions like autism, heart defects, or thyroid disease emerge and change with age, identifying critical windows for intervention and uncovering patterns that could lead to better preventive care.

Diversity is a cornerstone of this effort. The project is actively recruiting people from diverse racial, ethnic, and socioeconomic backgrounds to ensure that findings are applicable to everyone with Down syndrome. Secure data integration platforms are essential to this pillar’s success. The INCLUDE Data Hub serves as a centralized, cloud-based platform where approved researchers can explore aggregated data, use sophisticated tools to build virtual study cohorts, and connect with other resources, all while maintaining the strictest standards of participant privacy and data security.

This cohort building approach empowers researchers to ask and answer questions that were previously impossible, such as why some individuals with Down syndrome develop Alzheimer’s disease early while others are resilient, or what early life factors predict the development of autoimmune disorders later in life.

Pillar 3: Making Clinical Trials Inclusive

For decades, a profound injustice existed at the heart of medical research: people with intellectual and developmental disabilities were systematically excluded from clinical trials. The Include Project is actively dismantling this barrier, championing a new era of research where breakthrough treatments are accessible to all.

This pillar is dedicated to achieving true inclusivity. It’s not enough to simply allow people with Down syndrome to enroll; trials must be designed for their success. This involves adapting protocols by using visual aids and simplified language for informed consent, offering flexible scheduling to accommodate families, and actively involving caregivers and self-advocates in the study design process from the very beginning. Networks like the Down Syndrome Clinical Trial Network (DS-CTN) have been established to provide the infrastructure and expertise needed to run these inclusive studies effectively.

The project targets co-occurring conditions like Alzheimer’s disease, autoimmune disorders, and sleep apnea, ensuring that individuals with Down syndrome have equal access to trials for promising new drugs, therapies, and even vaccines. The NIH policy on the inclusion of individuals across the lifespan provides the regulatory framework, but the project goes further by fostering public-private partnerships to accelerate the translation of treatments from the lab to the clinic.

This pillar is founded on the principle that health equity is synonymous with better science. Inclusive trials yield more robust, generalizable, and real-world results. By championing this cause, the Include Project is not only improving the quality of its own research but also advancing justice for the Down syndrome community and setting a new, higher standard for all of medical research.

A Deeper Dive: Research Focus and Funding

The Include Project was born from the urgent need to address the complex web of interconnected health conditions faced by people with Down syndrome. Its mission is to untangle this web, understanding why certain conditions are more prevalent, how they interact, and how to treat them more effectively. The project’s research portfolio is a direct reflection of the community’s most pressing medical needs.

Targeting Co-occurring Health Conditions

Alzheimer’s disease research in the Down syndrome population is a powerful example of INCLUDE’s dual-benefit strategy. Nearly all adults with Down syndrome develop the characteristic brain changes of Alzheimer’s (amyloid plaques and tau tangles) by age 40. This is because the gene for the amyloid precursor protein (APP) resides on chromosome 21, and having a third copy leads to a lifetime of amyloid overproduction. This provides scientists with a unique and predictable human model to study the disease from its earliest preclinical stages. Findings on biomarkers, such as p-tau217 in the blood, are helping to predict disease progression and may lead to earlier detection and intervention for everyone at risk for Alzheimer’s.

Heart defects affect approximately half of all babies born with Down syndrome, often requiring complex open-heart surgery in the first months of life. The most common types are atrioventricular septal defects (AVSD). INCLUDE-funded research is investigating the genetic underpinnings of these defects, exploring genes like CRELD1, to understand why they are so common and to develop strategies for better prediction and management. Recent studies have also highlighted the need for lifelong cardiac screening, as undetected heart problems were found in up to 6% of older children and adults.

Autoimmune disorders are significantly more frequent because trisomy 21 disrupts immune system regulation, leading to an over-activation of the interferon pathway. This chronic state of immune alert, or “interferon signature,” contributes to high rates of conditions like celiac disease, autoimmune thyroiditis (Hashimoto’s), and the skin condition alopecia areata. Understanding this mechanism is not only key to helping people with Down syndrome but has also provided insights into other inflammatory conditions. Researchers are now testing targeted therapies, such as JAK inhibitors, to dampen this interferon response.

Leukemia risk is notably altered in children with Down syndrome. They have a much higher risk of developing certain blood cancers, particularly Acute Megakaryoblastic Leukemia (AMKL). Research has traced this risk to specific GATA1 gene mutations that occur in utero. This knowledge is paving the way for gentler, more targeted therapies that can reduce the harsh side effects of traditional chemotherapy, a critical goal given the increased sensitivity to treatment toxicity in this population.

The Cancer Paradox: While risks for blood cancers are high, individuals with Down syndrome have a remarkably lower risk of developing most solid tumors, including breast, prostate, and lung cancer. INCLUDE is funding research to understand this protective effect. Theories suggest that extra copies of tumor suppressor genes and anti-angiogenesis genes (which prevent tumors from developing a blood supply) on chromosome 21 may be responsible. Unlocking this mystery could lead to novel cancer prevention strategies for the general population.

Other Critical Conditions: The project’s scope is broad, addressing other vital areas such as:

• Sleep Disorders: Obstructive sleep apnea is extremely common and can exacerbate cognitive issues. Research is focused on better diagnostic tools and treatments tailored to the unique anatomy of individuals with Down syndrome.
• Musculoskeletal Issues: Problems like low muscle tone (hypotonia), joint laxity, and a higher risk of osteoporosis are being studied to improve physical therapy and long-term mobility.
• Metabolism and Obesity: Unique metabolic profiles contribute to higher rates of obesity. This research has already led to the creation of Down syndrome-specific growth charts and is exploring the underlying reasons for different energy expenditure patterns.

The Impact of Increased NIH Funding

For nearly two decades, Down syndrome was one of the least funded genetic conditions at the NIH relative to its prevalence. The 2018 Congressional directive, driven by years of relentless advocacy from organizations like the Global Down Syndrome Foundation and the National Down Syndrome Society, changed everything. NIH funding for Down syndrome research skyrocketed from a mere $18 million in 2009 to an unprecedented $133 million in 2024.

The Include Project itself has been the primary recipient and driver of this new investment, with its dedicated funding growing each year:

• 2018: $23 million of $60 million total NIH Down syndrome funding
• 2019: $35 million of $86 million total
• 2020: $60 million of $111 million total

This investment has yielded immediate and tangible returns. The number of Down syndrome-related research publications increased by a staggering 75 percent between 2014 and 2020. The funding surge enabled the NIH to issue numerous new Funding Opportunity Announcements (FOAs), which are formal calls for research proposals on specific topics. These FOAs have successfully drawn in top-tier researchers from diverse fields like immunology, oncology, and neuroscience, bringing fresh perspectives and advanced technologies to bear on the challenges of Down syndrome.

The DeOndra Dixon INCLUDE Project Act

The DeOndra Dixon Include Project Act is named in honor of DeOndra Dixon, the beloved sister of actor Jamie Foxx and a vibrant, passionate Global Ambassador for the Global Down Syndrome Foundation. DeOndra, who passed away in 2020, was a powerful self-advocate whose life exemplified the potential and joy of individuals with Down syndrome, while also highlighting the urgent need for better medical care and research.

The Act, which has garnered strong bipartisan support, aims to formally authorize the INCLUDE Project in law, ensuring its continuation and providing for sustained, predictable federal funding. This is critical because as life expectancy for people with Down syndrome has more than doubled to over 60 years today, new challenges related to aging, especially Alzheimer’s disease, have emerged. The legislation underscores the national commitment to this population and recognizes that consistent investment is the only way to solve complex, long-term medical challenges. The ongoing advocacy for this Act demonstrates the power of families and self-advocates to drive meaningful policy change, creating a virtuous cycle of funding, research, and improved lives. The Include Project stands as a testament to what can be achieved when science, advocacy, and resources unite to tackle our most complex medical challenges.

Collaboration and Data: The Keys to Findy

The remarkable progress of the Include Project is powered by a simple but revolutionary idea: the most profound discoveries happen through collaboration. The project is architected to break down the traditional silos that have long separated researchers, clinicians, families, and technology platforms. It fosters a dynamic ecosystem where data and ideas can be shared securely and efficiently, creating a whole that is far greater than the sum of its parts.

The Central Role of Data Hubs in the INCLUDE Project

At the heart of this collaborative model are powerful data platforms. A key foundational element is DS-Connect®: The Down Syndrome Registry. Launched in 2013, this online portal empowers self-advocates and their families to become direct partners in research. By creating a profile and sharing their health information in a confidential, de-identified manner, over 5,000 participants have contributed to a rich, real-world dataset that helps scientists understand the full spectrum of life with Down syndrome.

Building upon this foundation, the INCLUDE Data Coordinating Center (DCC) developed the Data Hub. This is not just a static repository but a sophisticated, cloud-based platform where scientists can access and analyze a massive, harmonized collection of data from multiple studies. The Data Hub contains diverse data types—including genomic, transcriptomic, proteomic, clinical, and imaging data—from thousands of participants. Its tools allow researchers to explore this data, identify potential participants for new studies (cohort discovery), and utilize advanced analytical workspaces. This open science approach, where data is made broadly available to qualified researchers, dramatically accelerates the pace of discovery.

This is where cutting-edge technologies like the ones we develop at Lifebit become critical. We enable Federated Data Analysis, a paradigm-shifting approach that allows analysis to be performed across multiple institutions without ever moving or copying the sensitive underlying data. Instead of pooling data in one place, the analysis query is sent securely to each data location, and only the aggregated, non-identifiable results are returned. This creates a Trusted Research Environment that maximizes research potential while upholding the highest standards of data privacy and governance. Such federated data hubs are dynamic platforms that accelerate discovery by making it easier and safer to find patterns, validate findings, and test new hypotheses across global datasets.

How the INCLUDE Project Partners with Families

The Include Project operates on the fundamental principle that the people it aims to serve must be partners in the process. Families and individuals with Down syndrome are not viewed as passive study subjects, but as active collaborators who bring invaluable lived experience and insight to the research enterprise.

Patient engagement is woven into the fabric of the project at every level. Families and self-advocates serve on community advisory boards, helping to set research priorities and ensuring that the questions being asked are relevant to their daily lives. They provide input on the design of clinical trials to make them more accessible and less burdensome. This co-design process ensures that the research addresses real-world concerns, from managing complex behaviors to improving communication skills.

DS-Connect® serves as a vital bridge in this partnership. It not only provides data for researchers but also serves the community directly by connecting families with clinical studies and trial opportunities for which they may be eligible. This two-way street of communication builds trust and empowers individuals to take an active role in their own healthcare and in the advancement of science.

This deep partnership transforms research from a top-down process into a collaborative journey. It ensures that the outcomes measured are meaningful to the community, such as improvements in daily functioning, independence, and overall quality of life. The result is research that is not only scientifically rigorous but also deeply humane and connected to the needs of the individuals and families it is meant to benefit, building the foundation of trust that is essential for long-term success.

Frequently Asked Questions about the INCLUDE Project

As the Include Project gains prominence, it naturally sparks curiosity and questions from families, clinicians, and the public. Here are detailed answers to some of the most common inquiries I encounter, aimed at providing a clearer understanding of this transformative initiative.

What is the primary goal of the INCLUDE Project?

The primary goal of the Include Project is to dramatically improve health, wellness, and quality-of-life for all individuals with Down syndrome by investigating co-occurring conditions across the lifespan and understanding the fundamental biology of trisomy 21.

This mission is pursued through its three-pillar strategy. The basic science pillar seeks to understand the how—how does an extra chromosome lead to specific health outcomes? The cohort-building pillar tracks the what and when—what conditions develop, when do they appear, and how do they progress over a lifetime? Finally, the clinical trials pillar tests the solutions—how can we effectively treat or prevent these conditions? Ultimately, the project aims to shift the paradigm of care from being reactive—treating problems as they arise—to being proactive and predictive, using precision medicine tailored to the unique biology of individuals with trisomy 21.

How can individuals with Down syndrome or their families get involved?

Getting involved is a straightforward and impactful way to contribute to the future of Down syndrome research and care. There are several key avenues for participation:

1. Join DS-Connect®: The Down Syndrome Registry: This is the most direct way to become a research partner. By visiting the DS-Connect® website, you can create a secure, private profile and complete a series of health surveys. This de-identified information is pooled with that of thousands of others to help scientists identify health trends and patterns. In return, the registry can notify you of clinical studies and research opportunities that might be a good fit for you or your family member. Your privacy is paramount, and you control how your information is used.

2. Participate in a Clinical Study: The INCLUDE Project funds a wide range of studies across the country. You can learn about actively recruiting studies through DS-Connect®, from advocacy organizations like the Global Down Syndrome Foundation and the National Down Syndrome Society, or at major medical centers with Down syndrome clinics.

3. Engage with Advocacy: Supporting the organizations that champion Down syndrome research is another powerful way to contribute. These groups play a critical role in advocating for federal funding, raising awareness, and ensuring the community’s voice is heard by policymakers and researchers.

Your participation, in any form, helps accelerate the pace of discovery and ensures that research is grounded in the real-world needs of the community.

How does research on Down syndrome benefit the general population?

Down syndrome research provides a unique and powerful window into human biology that generates discoveries with broad relevance for everyone. Because Down syndrome is a well-defined genetic condition, it acts as a “genetic magnifying glass,” allowing scientists to study the effects of gene dosage on complex diseases in a way that is not possible in the general population.

Here are a few concrete examples:

• Alzheimer’s Disease: People with Down syndrome almost universally develop the pathology of Alzheimer’s due to a third copy of the APP gene. This provides a predictable human model of the disease, allowing researchers to test preventative therapies and identify biomarkers (like blood tests) years before symptoms appear. These breakthroughs are directly applicable to the fight against Alzheimer’s in the general population.

• Cancer Prevention: Individuals with Down syndrome have a significantly lower risk of developing most solid tumors. Scientists are investigating the genetic reasons for this protection, focusing on extra copies of tumor-suppressor and anti-angiogenesis genes on chromosome 21. Unlocking this natural defense mechanism could lead to entirely new strategies for preventing cancer in everyone.

• Autoimmune Disorders: Research into the overactive interferon pathway in Down syndrome is helping to clarify the mechanisms behind many autoimmune diseases. Therapies being tested to calm this pathway in people with Down syndrome, such as JAK inhibitors, are also being explored for conditions like rheumatoid arthritis and even severe inflammatory responses to infections like COVID-19.

By investing in inclusive research, the Include Project creates a virtuous cycle where studying a specific population generates universal insights, proving that science that includes everyone benefits everyone.

Conclusion: Building a More Inclusive Future for Health Research

The Include Project represents far more than a well-funded research program; it marks a profound and permanent shift in medical science. It is a move away from fragmented studies and toward a unified, collaborative approach that puts people, in all their diversity, at the center of the scientific enterprise. Since its 2018 Congressional mandate, what began as an initiative for a specific community has rapidly evolved into a powerful movement and a blueprint for how to conduct inclusive, community-driven science in the 21st century.

By seamlessly integrating basic science research, large-scale data collection, and inclusive clinical trials, the Include Project is systematically breaking down the scientific and ethical barriers that have impeded progress for decades. It has transformed Down syndrome from one of the most underfunded genetic conditions to a leader in biomedical research.

The ripple effects of this work are remarkable. Studying the near-universal progression to Alzheimer’s disease or the innate protection from solid tumors in people with Down syndrome uncovers fundamental biological truths that can help everyone. This demonstrates a core principle: when no one is left behind in research, everyone benefits from the discoveries.

The technology enabling this revolution is as crucial as the science itself. Modern biomedical research, especially for complex conditions, requires secure, scalable platforms that can connect global data while respecting patient privacy. Federated AI platforms are game-changers in this domain. They allow researchers to ask questions of sensitive health information distributed across multiple hospitals and countries without ever moving or exposing the raw data.

At Lifebit, we are proud to build these secure, collaborative environments. Our work in creating federated data and genomics platforms directly supports the vision of initiatives like the Include Project. We ensure that researchers have the tools they need to collaborate effectively and safely across institutional and geographic boundaries. When data can flow securely, discoveries happen faster.

The future we are building together is one where every person has a seat at the research table, where clinical trials are designed for universal accessibility, and where families and self-advocates help shape the scientific questions that matter most. This vision extends far beyond Down syndrome. The Include Project provides a proven model for how to combine community engagement, sustained investment, and cutting-edge technology to accelerate progress for other rare diseases and complex conditions. We are committed to powering this next generation of collaborative research across Federal Health and beyond, driven by the conviction that better, faster science happens when everyone is included.

The Include Project began with the simple, powerful idea that people with Down syndrome deserve the full attention and benefit of modern medical research. It has become definitive proof that inclusive science is not just the right thing to do—it’s the smartest way to build a healthier future for all.