Early-onset Alzheimer’s: new drug shows promise in slowing the disease

Alzheimer’s disease is usually associated with old age. But around 5%-10% of all Alzheimer’s cases occur in people under the age of 65. Early-onset Alzheimer’s disease progresses more rapidly and often strikes people in the prime of their lives. Treatment options remain limited.

But new data from a recent clinical trial suggests that a previously discontinued experimental drug, called gantenerumab, could help. The study found that gantenerumab reduced the buildup of amyloid plaques – one of the hallmarks of Alzheimer’s disease – in the brain. This may help slow cognitive decline in people with early-onset Alzheimer’s.

Early-onset Alzheimer’s is often linked to genetic mutations in three specific genes. These mutations cause the brain to produce excessive amounts of amyloid beta, a protein that clumps together to form plaques. These plaques disrupt brain function, leading to memory loss.

Early-onset Alzheimer’s advances quickly – and the rapid decline is devastating. That’s why researchers are racing to find treatments that can slow the disease.

Read more: Young-onset Alzheimer’s can be diagnosed from as early as 30 – and the symptoms are often different

The recent clinical trial was a randomised, placebo-controlled study to evaluate gantenerumab’s effects on people with early-onset Alzheimer’s. Researchers monitored changes in the participants’ cognitive abilities, and also used brain imaging and blood biomarkers (the presence of specific proteins in the blood which are linked to Alzheimer’s), to track the disease’s progress throughout the study.

The trial included 73 participants with rare inherited genetic mutations known to cause early-onset Alzheimer’s. These participants were either asymptomatic or had mild Alzheimer’s symptoms at the start of the study.

The results were intriguing. In a subgroup of 22 participants, who hadn’t had any cognitive issues at the start of the study, taking the treatment for an average of eight years reduced the risk of developing symptoms from a nearly 100% likelihood, to 50%. Brain scans also showed a notable decrease in amyloid buildup.

Immune defenders

Gantenerumab is a monoclonal antibody – a lab-engineered protein designed to attach to amyloid beta in the brain. By binding to these plaques, it signals the immune system to clear them away. This may potentially slow Alzheimer’s progression.

The drug works by engaging microglial cells. These are the brain’s primary immune defenders. Microglia constantly monitor the brain for damage and remove harmful substances, including amyloid beta. However, in people with Alzheimer’s disease, microglia often fail to clear plaques efficiently. Gantenerumab enhances this natural defence mechanism by tagging amyloid plaques, making them easier for the microglia to recognise and break down.

Amyloid beta is thought to play a central role in Alzheimer’s by triggering inflammation, interfering with cell communication and ultimately killing neurons. By removing these plaques, gantenerumab may help to protect brain function. However, it doesn’t reverse existing damage – which is why early intervention is critical.

An advantage of gantenerumab is that it can cross the blood-brain barrier – the protective shield that blocks many drugs and harmful substances from reaching the brain. This allows it to act directly on amyloid plaques, making it more effective than some earlier treatments that struggled with drug delivery.

But as promising as these results are, gantenerumab isn’t without risks.

A major concern is amyloid-related imaging abnormalities. These are swelling or small spots of bleeding in the brain that show up on MRI scans. This is a common side-effect of amyloid-targeting therapies.

In this latest trial, 53% of participants experienced these amyloid-related imaging abnormalities, including small brain bleeds in 27% of participants, brain swelling in 30% of participants and iron deposits from bleeding in 6%. While no participants had major brain haemorrhages or died from the treatment, these side-effects remain a serious concern – requiring regular monitoring through brain scans.

Another limitation is the modest cognitive benefit observed in the trial. While gantenerumab reduced amyloid plaques, the extent to which this translates into meaningful improvements in memory and thinking skills remains unclear.

Gantenerumab is also expensive to manufacture, which could make widespread access difficult if it gains regulatory approval. As this is an experimental drug, we do not currently know how much it would cost. But other similar anti-amyloid therapies, such as donanemab, currently cost around £25,000 per patient per year.

The study also had a small sample size and only focused on a rare genetic form of early-onset Alzheimer’s. More research is needed to see how these results may apply to the wider dementia community.

The future of treatment

Although the trial was terminated early after the study’s sponsor pulled out, these findings contribute to the ongoing debate over the causes of Alzheimer’s disease.

According to the amyloid hypothesis, the buildup of amyloid plaques in the brain is the main cause of Alzheimer’s disease. Clearing these plaques will slow the disease’s progression. The success of the Alzheimer’s drugs lecanemab, donanemab and now gantenerumab, lend themselves to this theory.

This study also underscores the importance of early diagnosis. Amyloid-targeting therapies appear to work best in the early stages of Alzheimer’s, before significant brain damage occurs. Advances in biomarker testing – including blood tests and brain scans – could help identify at-risk people sooner. This would improve the effectiveness of drugs such as gantenerumab.

Although gantenerumab is not a cure and was discontinued by its manufacturer in 2022 because it failed to demonstrate efficacy in slowing the progression of Alzheimer’s disease, this new data could perhaps lead to gantenerumab being manufactured again. It also represents another step forward in the fight against Alzheimer’s.

Alzheimer’s research is advancing faster than ever before. Whether a success or a setback, each new study adds to our understanding of the disease and brings us closer to more effective treatments. For now, the gantenerumab trial offers a hopeful sign that scientists are making progress in slowing the course of this devastating condition.

Rahul Sidhu does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.