In anticipation of new opportunities for adults with Down syndrome to participate in clinical trials for Alzheimer’s therapies, LuMind IDSC  developed a guide introducing families to the differences in the therapeutic approaches.  Download the full guide here, or read on…

People with Down syndrome face a heightened risk of developing Alzheimer’s disease (AD) due to their unique genetic makeup. That makes them more vulnerable to early-onset AD and significantly increases their likelihood of developing AD in their lifetime, compared to the general population. While researchers have made progress in understanding the biological mechanisms underlying Alzheimer’s, much remains to be learned about how to intervene effectively to protect brain health in this community. Today, multiple research efforts are underway to identify effective therapeutic approaches for individuals with Down syndrome, each targeting the problem in a distinct and specialized way.

Understanding the differences among these new therapies is crucial—not only in terms of how they are meant to prevent or slow the progression of AD, but also in the drug delivery methods. Some therapies aim to address the problem at its source, while others focus on clearing existing damage. By exploring these nuances, caregivers and self-advocates can better appreciate the research underway and the steps scientists are taking to potentially improve outcomes for individuals with Down syndrome.

The initial Aß clumps can grow into larger clumps that can eventually be seen by a microscope. The larger clumps are called Aß plaques (shown in red, below), which can start to build up around neurons, the cells in the brain that carry our thoughts and store our memories (shown in lavender, below). When smaller clumps and plaques build up in the brain, they can start to interfere with memory and thinking, similar to how a factory with cluttered assembly lines and blocked pathways can’t function effectively. This blockage can lead eventually to Alzheimer’s disease.

People with Down syndrome are more prone to Aß clumping, which is why they have a >90% lifetime risk of developing Alzheimer’s dementia. As such, scientists are working hard to find ways to prevent these Aß clumps and plaques from forming or to remove them after they accumulate, in order to protect their brain health.

Researchers are currently investigating at least three types of therapies that address this buildup of Aß plaques. Each therapy seeks to intervene at different points in the plaque accumulation process, and each involves a different mechanism of intervention.

These therapies are still being studied, and researchers are working to understand how effective and safe they are for people with Down syndrome-associated Alzheimer’s disease (DS-AD).

While the treatments show promise, it’s important to remember that the goal of these studies is to gather knowledge, not to promise immediate results or cures. Each study is a step toward better understanding how to support brain health in Down syndrome and prevent or delay Alzheimer’s disease.

Families should always consult their loved one’s doctor when considering clinical research participation.

Overview of Investigational Therapy Types:

• Antisense Oligonucleotides: These investigational therapies aim to address the root cause of DS-AD by reducing the expression of the Amyloid Precursor Protein (APP) gene. People with Down syndrome are born with three copies of the APP gene, which produces a protein that can form harmful amyloid beta plaques. ASO is delivered by lumbar puncture.
• Vaccine Immunotherapies: These therapies train the immune system to identify and remove harmful forms of amyloid beta from the brain, similar to how a flu vaccine helps the body recognize and fight the flu virus. Vaccine immunotherapies are delivered by intramuscular injection.
• Antibody Immunotherapies: These therapies identify and bind to harmful forms of amyloid beta, signaling immune cells to help remove the plaques from the brain that are bound to the antibody. Antibody immunotherapies are delivered via IV infusion.

Overview of Methods of Delivery:

• Lumbar Puncture: A needle is inserted into the lower back to deliver the therapy directly into the cerebrospinal fluid surrounding the brain and spinal cord. This method, sometimes referred to as “intrathecal administration,” is often used when the treatment needs direct access to the brain.
• Intramuscular Injection: A shot is administered into the muscle, similar to a flu vaccine. The medication is absorbed into the bloodstream from the muscle tissue.
• Intravenous Infusion: A therapy delivered directly into a vein through an IV drip, allowing immediate entry into the bloodstream.

Defining Study Phases:

• Phase 1 or Phase 1b: An early-stage study primarily focused on evaluating the safety and tolerability of a drug or treatment in a small group of participants. It often includes preliminary assessments of how the body processes the drug and potential side effects.
• Phase 1b/2: A combined phase continuing safety testing from Phase 1 while also beginning to assess the treatment’s effectiveness like a Phase 2 study. This phase provides early insights into whether the treatment impacts the disease process the way it was intended.
• Phase 2: A mid-stage study designed to evaluate the effectiveness of a drug or treatment in a larger group of participants. It also continues to assess safety and aims to identify the optimal dosage and administration methods. Phase 2 provides critical data on whether the treatment is showing the desired effects and helps refine the design for larger trials before FDA approval (Phase 3).
• Phase 3: A late-stage study conducted with a much larger group of participants to confirm the drug or treatment’s effectiveness and monitor side effects. Phase 3 trials provide the evidence that the FDA will consider when deciding whether or not to approve the new treatment for general use.
• Phase 4: Conducted after a drug or treatment has been approved for public use, focusing on long-term safety and effectiveness in a larger, real-world population. In some cases, such as with Down syndrome, Phase 4 trials may be conducted if the drug was not specifically tested in this population during earlier phases.

Placebo Controlled:

• Non-Placebo Controlled: All participants receive the investigational drug treatment with no comparison to an inactive substance. This design is often used in early-phase trials (such as Phase 1) focused on safety.
• Placebo Controlled: Some participants receive the investigational treatment, while others receive a placebo (an inactive substance) to compare results. This design helps ensure any effects observed are due to the treatment itself rather than natural changes or psychological factors like the “placebo effect.”

Randomization:

• Randomized Clinical Trial: Participants are assigned to different groups by chance (randomly), ensuring fairness and reducing bias. This helps researchers determine whether the treatment is truly effective.
• Non-Randomized Clinical Trial: Participants are assigned to groups based on specific criteria rather than by chance. While this approach may be necessary in some cases, it can introduce bias and make results less reliable, but is appropriate for observational studies like a Natural History Study.

Blinding:

• Blinded Clinical Trial: Participants (and sometimes researchers) do not know which treatment they are receiving. This helps prevent expectations or biases from influencing results. Blinding can be single-blind (only participants don’t know) or double-blind (both participants and researchers don’t know).
• Open-Label Clinical Trial: Everyone involved knows which treatment is being given. This design is often used when blinding isn’t possible, such as when studying a drug with noticeable effects or long-term safety.

MRI/PET Scans:

• MRI Scans (Magnetic Resonance Imaging): MRI scans use magnets and radio waves to create detailed images of the brain. They help researchers monitor changes in brain size and define the brain structure to identify which parts of the brain are affected by Alzheimer’s disease.
• PET Scans (Positron Emission Tomography): PET scans involve a safe, low-dose injection of a tracer that highlights amyloid plaques in brain images. These plaques are harmful proteins linked to Alzheimer’s disease and help researchers assess the presence of disease-related changes in the brain.
• Preparing for brain scans: LuMind IDSC has two videos designed to help adults with Down syndrome and their families prepare for MRI & PET. Watch Samuel & his dad at Samuel’s scan appointments, here: What to Expect Video Series