A Glimmer of Hope: Experimental Drug Shows Promise in Delaying Genetically Predetermined Alzheimer’s

Alzheimer’s disease, a devastating neurodegenerative disorder, has long been a formidable challenge for researchers and clinicians alike. Characterized by progressive cognitive decline and memory loss, it robs individuals of their independence and profoundly impacts their families. However, recent developments in Alzheimer’s research offer a glimmer of hope, suggesting that we may be on the verge of a pivotal moment in our understanding and treatment of this debilitating condition.

This week, scientists released clinical trial data presenting early evidence that it’s possible to delay the onset of symptoms in individuals genetically predisposed to developing Alzheimer’s at a young age. The study, led by researchers at the Washington University School of Medicine, investigated the potential of an experimental anti-amyloid drug called gantenerumab to help people with an inherited form of Alzheimer’s.

The study’s primary objective was to determine whether gantenerumab could effectively target and reduce amyloid plaques, a hallmark of Alzheimer’s disease, in the brains of individuals at high risk of developing the condition due to their genetic makeup. Amyloid plaques are formed by the accumulation of misfolded beta-amyloid proteins, which clump together and disrupt normal brain function.

The results of the clinical trial were particularly encouraging in a subset of patients who received the drug for the longest duration. In this group, gantenerumab appeared to reduce the risk of developing Alzheimer’s symptoms by an impressive 50%. While these findings are preliminary and require further investigation, they have sparked cautious optimism among experts in the field.

Dr. Thomas M. Wisniewski, the director of the Center for Cognitive Neurology at NYU Langone Health, who was not involved in the research, expressed his enthusiasm, stating that the results "make it clear that there is good hope that treatment of [Alzheimer’s] pathology in the preclinical stages of pathology may be effective at slowing or preventing disease onset."

Gantenerumab belongs to a class of drugs known as anti-amyloid antibodies. These antibodies are designed to specifically target and remove beta-amyloid plaques from the brain. The underlying hypothesis is that by eliminating these plaques, it may be possible to halt or slow down the progression of Alzheimer’s disease.

However, the journey of anti-amyloid drugs in Alzheimer’s research has been fraught with challenges. Many promising candidates have initially shown encouraging results but have ultimately failed in larger clinical trials involving individuals already experiencing Alzheimer’s symptoms. Gantenerumab itself faced a setback in late 2022 when pharmaceutical company Roche discontinued its development after two Phase III trials yielded disappointing results.

Despite these past failures, the field has not been deterred, and recent anti-amyloid drugs have demonstrated a modest but noticeable effect in slowing down Alzheimer’s. These drugs have even gained approval from the Food and Drug Administration (FDA), marking a significant milestone in the fight against Alzheimer’s.

Building on these advancements, researchers at WashU Medicine and other institutions hypothesized that anti-amyloid treatment might be more effective if administered well before the onset of Alzheimer’s symptoms. This led to the initiation of prevention trials in individuals with dominantly inherited Alzheimer’s, a genetic condition that almost guarantees the development of dementia between the ages of 30 and 50.

The current trial, which began in 2012, aimed to assess the efficacy of gantenerumab in this high-risk population. While most of these trials have not yielded conclusive results, the gantenerumab study has shown some potential.

The initial findings from the gantenerumab study, which concluded in 2020, revealed that the drug effectively reduced amyloid levels in the participants’ brains. However, it was too early to determine whether this reduction would translate into a delay in symptom onset, as most participants were not expected to develop symptoms for another 10 to 15 years.

To address this uncertainty, the researchers decided to extend the study and provide gantenerumab to all participants, including those who had previously received a placebo or another drug. The latest results from this extension study, published in The Lancet Neurology, have generated excitement within the scientific community.

According to Randall J. Bateman, a professor of neurology at WashU Medicine and the senior author of the study, "Everyone in this study was destined to develop Alzheimer’s disease and some of them haven’t yet. We don’t yet know how long they will remain symptom-free—maybe a few years or maybe decades."

While the findings are promising, it’s crucial to acknowledge the limitations of the study. Dr. Wisniewski points out that the findings only hint at a potential preventative benefit. Although the drug may have reduced the risk of cognitive decline in the overall group of asymptomatic individuals, this reduction was not statistically significant, possibly due to the relatively small sample size of 73 participants.

In the subset of asymptomatic patients who received the drug for the longest duration, approximately eight years on average, gantenerumab appeared to reduce their expected chances of cognitive decline by 50%. However, this subset only included 22 patients, further highlighting the need for larger studies.

Furthermore, the trial was terminated prematurely for many participants due to Roche’s decision to discontinue the development of the drug, and some individuals dropped out for other reasons.

In terms of safety, gantenerumab appeared to be generally safe and tolerable, although about one-third of the participants developed amyloid-related imaging abnormalities (ARIAs), which are markers of swelling or bleeding in the brain. ARIAs are a known side effect of anti-amyloid drugs, but most episodes are unnoticed by patients. Two patients did experience severe ARIAs, which prompted the researchers to discontinue treatment, after which they recovered. No life-threatening events or deaths were reported during the study.

Overall, the study does not provide definitive proof that anti-amyloid drugs can prevent Alzheimer’s when administered long before the onset of symptoms. However, given the inevitability of the genetic form of the disease, these results represent the first evidence from a clinical trial suggesting that it could be treated.

Coupled with the earlier approvals of lecanemab and donanemab for the more common form of Alzheimer’s, these findings suggest that there may be a real opportunity to make a difference in the lives of individuals at risk of developing this devastating condition.

Sam Grady, associate director of the Alzheimer’s Disease Research Center at Mount Sinai, emphasized the significance of the study, stating, "We already know from the lecanemab and donanemab data that anti-amyloid antibodies (AAAs) can slow progression of common, sporadic Alzheimer’s. This paper focuses on using a different AAA (gantenerumab) to demonstrate a similar phenomenon is true in genetic early onset Alzheimer’s."

Both Grady and Wisniewski, along with the study researchers, agree that this is just the beginning. There are ongoing prevention trials for both early-onset and common Alzheimer’s, including several being conducted by WashU through its Dominantly Inherited Alzheimer Network-Trials Unit. These trials are evaluating both approved and newer experimental anti-amyloid drugs that could potentially offer even greater protective benefits than gantenerumab. The researchers were also able to transition many of their patients from the original extension study to lecanemab, although the data from this phase is still being analyzed.

In conclusion, while much work remains to be done, the recent findings regarding gantenerumab offer a glimmer of hope for individuals at risk of developing Alzheimer’s disease. These early results suggest that it may be possible to delay the onset of symptoms in genetically predisposed individuals, potentially altering the course of this devastating condition. As research continues and new therapies are developed, there is reason to believe that we may be on the cusp of a new era in Alzheimer’s prevention and treatment.