Alzheimer’s risk cut in half by drug in landmark prevention trial

For the first time, researchers have evidence that removing amyloid plaques from the brain before symptoms appear can reduce Alzheimer’s risk by roughly half in people with a rare genetic form of the disease. A clinical trial published in The Lancet Neurology found that long-term, high-dose treatment with the antibody drug gantenerumab significantly delayed the onset of dementia in people who carry mutations that make Alzheimer’s disease near-certain. The findings mark the clearest signal yet that early intervention — years before symptoms emerge — can change the course of the disease.

• The trial focused on people with dominantly inherited Alzheimer’s disease (DIAD), a rare genetic form caused by mutations in the PSEN1, PSEN2, or APP genes that accounts for less than 1% of all Alzheimer’s cases but causes the disease with near-certainty, typically in a person’s 40s or 50s.
• Participants who achieved near-normal amyloid levels or began treatment many years before their expected symptom onset saw roughly a 50% reduction in Alzheimer’s risk of progressing to dementia, according to the DIAN-TU trial led by Washington University School of Medicine in St. Louis.
• Gantenerumab was discontinued by its manufacturer for broader Alzheimer’s populations in 2022, but these findings have prompted researchers to launch a new follow-up study — the DIAN-TU Amyloid Removal Trial — to confirm and extend the results.

The people who enrolled in this trial knew, with unusual certainty, what was coming. Carriers of DIAD mutations face a trajectory that researchers can predict within a few years: amyloid begins accumulating in the brain roughly two decades before symptoms appear, followed by cognitive decline that leads to dementia at a relatively predictable age. That predictability, grim as it is, made this population the ideal test case for a question that has driven Alzheimer’s research for decades — whether clearing amyloid from the brain early enough can prevent the disease from taking hold. It is part of a broader wave of good news in global health that rarely makes the front page.

How long-term amyloid removal reduces Alzheimer’s risk

The DIAN-TU trial, launched in 2012, initially tested gantenerumab and another antibody called solanezumab against placebo in people who were between 15 years before and 10 years after their expected age of symptom onset. The early phase of the trial did not show significant cognitive benefit — partly because participants without symptoms hadn’t yet declined, making improvement impossible to measure. That led researchers to launch an open-label extension in which all participants received gantenerumab at escalating doses up to 1,500 milligrams every two weeks, far higher than earlier in the trial.

The extension enrolled 73 participants and ran for up to three years before being stopped early — not because of safety concerns, but because gantenerumab’s manufacturer, Roche, discontinued the drug after it failed to meet endpoints in larger trials of common late-onset Alzheimer’s. The DIAN-TU researchers continued their analysis using external controls drawn from participants in a related observational study who had received no treatment. Among those who achieved near-normal amyloid levels or who had been treated for many years before their expected symptom onset, the data showed roughly a 50% reduction in Alzheimer’s risk compared to untreated controls.

The researchers are careful about what the finding does and does not prove. According to the study authors, the results are statistically uncertain due to the open-label design and the use of external rather than randomized controls. The overall group of participants did not show statistically significant clinical benefit — the signal emerged specifically in those who cleared amyloid most completely and those treated furthest from their expected symptom onset. The authors call the findings clinically meaningful but say they require confirmation in longer, more rigorous trials.

What this means for Alzheimer’s risk research and prevention

What makes these results significant extends beyond gantenerumab itself, which is no longer commercially available. The finding matters because it provides the first evidence from a prevention trial that removing amyloid before symptoms appear can alter the disease’s course in people who are biologically certain to develop it. That is a different claim from anything previously demonstrated — earlier anti-amyloid drugs showed they could slow decline in people who already had symptoms, but not that they could prevent the disease from emerging at all.

DIAD affects fewer than 1% of Alzheimer’s patients, but its predictability has long made it the most valuable test population for prevention research. If the amyloid hypothesis holds in people who are genetically certain to develop the disease, it strengthens the case for testing the same approach in people at earlier stages of the far more common late-onset form. The DIAN-TU Amyloid Removal Trial, now underway, aims to answer how much amyloid must be removed, how early, and for how long to produce durable protection.

Progress against Alzheimer’s is part of a documented pattern of improving health outcomes worldwide. Global cancer death rates have reached record lows, and the global suicide rate has fallen nearly 40% since 1995 — evidence that sustained research and intervention can move numbers that once seemed immovable. Alzheimer’s, which affects more than 55 million people worldwide, has long been the most stubborn exception to that pattern.

The 55 million people currently living with dementia are not going to be helped by a discontinued drug. But the researchers at Washington University and their collaborators across 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the U.K., and the U.S. have established something that will shape the field for years: that the window for meaningful intervention exists, that it opens before symptoms appear, and that reaching near-normal amyloid levels may be the threshold that matters. The next generation of trials will be designed around that target.

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This story was originally reported by The Lancet Neurology.