Stopping Alzheimer’s before it starts: Early treatment shows potential

A new study indicates that an experimental drug can reduce Alzheimer’s-related dementia risk in those certain to develop symptoms in their 30s, 40s, or 50s. 

If confirmed, the results suggest that removing amyloid plaques from the brain long before memory issues occur may delay or even avert the onset of Alzheimer’s dementia.

Individuals with early Alzheimer’s risk

The international research team was led by the Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU) at Washington University School of Medicine in St. Louis.

The study was focused on 73 people carrying rare, inherited mutations that substantially increase the production of amyloid in the brain – mutations that guarantee them Alzheimer’s disease in middle age. 

Over two decades, the Knight Family DIAN-TU has worked to find therapies aimed at preventing or slowing disease progression in such families.

For a subgroup of 22 participants who exhibited no cognitive problems at the beginning of the study and who received the drug the longest (an average of eight years), the treatment decreased the risk of developing symptoms from 100% to approximately 50%. 

This calculation, supported by multiple sensitivity analyses, suggests that early intervention may give participants additional healthy years, although the duration of protection is not yet known.

Giving people more years of healthy life 

Study senior author Randall J. Bateman, a professor of neurology at WashU Medicine, noted that everyone in the 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. In order to give them the best opportunity to stay cognitively normal, we have continued treatment with another anti-amyloid antibody in hopes they will never develop symptoms at all,” said Bateman. 

“What we do know is that it’s possible at least to delay the onset of the symptoms of Alzheimer’s disease and give people more years of healthy life.”

Eliminating amyloid plaques in the brain 

These results bolster the amyloid hypothesis, which proposes that Alzheimer’s disease begins with an accumulation of amyloid plaques in the brain. Researchers have speculated that eliminating those plaques, or halting their formation, could keep dementia at bay.

For this work, Bateman and colleagues investigated whether an experimental anti-amyloid therapy might prevent Alzheimer’s dementia. 

The study sample comprised people who initially joined the Knight Family DIAN-TU-001 trial (the world’s first Alzheimer’s prevention study) and then continued into an extension phase where they received an anti-amyloid medication.

Insufficient evidence of Alzheimer’s prevention 

Knight Family DIAN-TU-001 began in 2012 to evaluate anti-amyloid therapies as preventive measures for Alzheimer’s in participants with no or very mild symptoms and lying between 15 years before and 10 years after their expected onset age. 

Results shared in 2020 indicated that one drug – gantenerumab, made by Roche/Genentech – lowered brain amyloid levels and changed certain Alzheimer’s biomarkers. 

However, researchers found insufficient evidence of cognitive benefit because participants without symptoms remained stable, whether on drug or placebo.

Extending the trial

To refine and continue testing, the team initiated an open-label extension of the trial. All individuals carrying a high-risk Alzheimer’s mutation could join – regardless of original trial assignment. 

Because everyone in the extension received the study drug, the researchers compared them with participants in a separate, untreated observational study and with some participants who had received placebo but did not enter the extension.

Although the extension was designed to run three years, it ended mid-2023 after Roche/Genentech stopped gantenerumab’s development in late 2022, owing to Phase III results in early symptomatic Alzheimer’s failing to meet the main endpoint of slowing clinical decline. 

By that time, most extension participants had received gantenerumab for an average of 2.6 years.

Analyses of that extension data revealed that removing amyloid far in advance of symptoms potentially delayed disease onset and dementia progression, especially among participants with no initial symptoms who received the drug for about eight years.

In that subgroup, the drug halved the risk of becoming symptomatic.

Treating early Alzheimer’s

Though gantenerumab and other anti-amyloid therapies can trigger ARIA (amyloid-related imaging abnormalities) visible on brain scans, most cases yield no clinical symptoms and resolve on their own. 

Two participants developed severe ARIA and had to discontinue the therapy but subsequently recovered. No life-threatening events or deaths occurred, and the overall safety profile matched other gantenerumab research.

Once Roche ended gantenerumab, most participants switched to lecanemab – an anti-amyloid agent recently authorized by the U.S. Food and Drug Administration for slowing cognitive decline in symptomatic Alzheimer’s. 

The newly launched Knight Family DIAN-TU Amyloid Removal Trial will also use lecanemab to see how effectively it prevents or postpones Alzheimer’s in these high-risk families.

While the trial focuses on genetically caused early-onset Alzheimer’s, the team believes that the results will inform prevention and treatment for all forms of Alzheimer’s disease. 

Both early- and late-onset disease begin with amyloid accumulation roughly 20 years before clinical symptoms arise. Data from early-onset mutation families has proven consistent with late-onset Alzheimer’s trials.

Optimism for therapeutic breakthroughs 

“If late-onset Alzheimer’s prevention trials have similar results to the DIAN-TU trials, there soon could be Alzheimer’s preventions available for the general population,” Bateman said. 

“I am highly optimistic now, as this could be the first clinical evidence of what will become preventions for people at risk for Alzheimer’s disease. One day soon, we may be delaying the onset of Alzheimer’s disease for millions.”

While gantenerumab has been withdrawn from development, other antibodies targeting amyloid remain under evaluation for Alzheimer’s. 

Observers within the research community say the findings demonstrate the significance of focusing on early removal of brain amyloid for potentially avoiding or postponing dementia, fueling optimism for near-future therapeutic breakthroughs.

The study is published in the journal The Lancet Neurology.

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