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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…

Key differences among the current and emerging Alzheimer’s clinical trials in Down syndrome

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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.

Why are adults with Down syndrome affected by Alzheimer's disease at such a high rate?

The answer can be found in the genetic makeup of most people with Down syndrome.

Every cell in the human body has a set of instructions (“genes”) that tell cells how to make proteins—those tiny building blocks that help our bodies function properly. People with Down syndrome have an extra copy of a particular gene called the APP gene (illustrated by the blue helix at right), which gives their bodies an extra set of instructions for making a protein called amyloid precursor protein (APP), a protein made in the brain that helps cells function normally.

Imagine a factory that typically handles two orders for APP, producing just enough to meet the body’s needs. In people with Down syndrome, the factory gets three orders instead of two, causing it to overproduce APP—like an assembly line working overtime and creating a surplus of product (in blue in illustration at right).

After APP is made, it naturally breaks down into smaller pieces. Some of those pieces are called amyloid beta (Aß, shown in red in the illustration below). In the brains of people without Down syndrome, extra or used Aß typically gets cleared away by the brain’s natural cleanup systems. However, in the brains of people with Down syndrome, the overproduction of APP protein means that extra Aß is made starting at birth, which can overwhelm these brain cleanup systems.

It’s like the factory’s assembly line is running so fast that too many parts pile up, and the janitors (the brain’s cleanup system) can’t keep up with the extra Aß . Some of these extra Aß pieces can misfold and begin to stick together into clumps (shown in red, below). Once these clumps form, they act like sticky residue on the factory floor, making it harder for normal operations to continue.

vert extra gene to extra protein

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.

horiz process to plaques

How do the different types of therapies intervene in the process of Aß clumping?

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.

Antisense Oligonucleotides (ASOs)

Imagine a supervisor stepping in to slow down the factory’s production line by cancelling the extra APP order. ASOs work at the genetic level to reduce the amount of APP protein produced, which is intended to lower the amount of Aß made. This subsequently may prevent excess Aß clumping and reduce plaque levels, which together may slow down disease progression.

To return to our analogy, the ASO helps ensure the factory doesn’t generate an overwhelming surplus of components that could lead to assembly line clutter.

The HERO study, sponsored by Ionis Pharmaceuticals, is an active clinical trial studying the safety and tolerability of an ASO intervention. The mechanism Ionis is testing is administered into the spine (intrathecal), by lumbar puncture, which allows the ASO to be delivered directly to the brain via spinal fluid.

unlabeled ASO silences

ASOs are designed to silence the extra gene that causes overproduction of APP

Vaccine Immunotherapies

Vaccines train the body’s “security team” to patrol the factory floor, identifying and removing harmful Aß clumps and plaques. The security team inspects the assembly line for faulty parts and clears them out early, while also recognizing and breaking down larger blockages that have already formed.  In this way, vaccines act as both preventative measures and cleanup crews.

The ABATE study, sponsored by AC Immune, is currently seeking to determine the safety, tolerability, immunogenicity, and effects of vaccine immunotherapy ACI-24.060 in adults with Down syndrome. This vaccine candidate is delivered, like any other vaccine, by injection into a muscle; the same way flu vaccines are administered.

unlabeled vaccines

Vaccines are designed to train the immune system to identify and remove harmful forms of amyloid beta from the brain

Antibody Immunotherapies

Antibody treatments are like specialized “cleaning crews” that step in when harmful clumps of Aß plaques have already built up. These crews target the stubborn blockages, breaking them down and removing them from the factory floor, much like clearing a clogged assembly line to restore functionality.

Commercially known as Leqembi (sold by Eisai and Biogen) and Kisunla (sold by Lilly), anti-amyloid antibodies are currently approved by the FDA for use by neurotypical adults with early Alzheimer’s disease.  The upcoming ALADDIN study will be the first investigation of the antibody Kisunla in a cohort of people with Down syndrome.

unlabeled antibodies

Antibodies identify, break down, and remove amyloid plaques

What's next in the treatment of DS-AD?

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.

What are the differences in the current and upcoming clinical trials in Down syndrome-associated Alzheimer’s disease?

HERO Study

ABATE Study

ALADDIN Study

Study Sponsor Ionis Pharmaceuticals AC Immune Alzheimer’s Clinical Trials Consortium – Down Syndrome (ACTC-DS)
Therapy Being Investigated ION269 ACI-24.060 Donanemab
(Kisunla, by Lilly)
Type of Intervention Antisense Oligonucleotide Vaccine Immunotherapy Antibody Immunotherapy
Aim of the Study To evaluate the safety and tolerability of ION269 in adults with Down syndrome To assess the safety, tolerability, immunogenicity, and pharmacodynamic effects of ACI-24.060 in adults with Down syndrome To evaluate the safety, tolerability, and efficacy of Donanemab in adults with Down syndrome
Phase Phase 1b Phase 1b/2 Phase 4
Has this therapy been studied in Down syndrome previously? No No, but AC Immune conducted a Phase 1 study in Down syndrome with an earlier version of the vaccine No, approved for treatment of early Alzheimer’s disease but not tested in Down syndrome individuals yet
Is the study Placebo-Controlled? No, not Placebo-Controlled Yes, Placebo-Controlled Yes, Placebo-Controlled
Method of Delivery Lumbar Puncture Intramuscular Injection Intravenous Infusion
Enrollment Criteria People with DS between ages of 35 and 55, who do not have dementia, have a study partner, and have evidence of amyloid pathology. People with DS between ages of 35 and 50, who do not have dementia and have a study partner. Participants between ages 35 and 39 require evidence of amyloid pathology. To be announced
Requires MRI/PET scans? MRI + PET MRI + PET To be announced
Expected Enrollment 30 80 To be announced
Participation Duration ~1 year 2 years To be announced
Active Locations US, Spain US, UK, Spain To be announced
Date of Study Completion 2027 2026 To be announced
Clinicaltrials.gov link https://clinicaltrials.gov/study/NCT06673069 https://clinicaltrials.gov/study/NCT05462106 To be announced

Key terms, concepts, and facts related to new DS-AD clinical trials

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
Study Chart