To beta-amyloid or not to beta-amyloid? An innovative meta-analysis offers new insight into Alzheimer's drugs

aging man A new approach from UCSF researchers will help scientists more rapidly assess whether we are on the right track for developing drugs to treat Alzheimer’s disease. Currently, medications approved for Alzheimer’s disease only help to manage symptoms but do not change the disease course. The hunt for for effective medications has centered on drugs that target beta-amyloid, a protein that builds up in the brains of people with Alzheimer’s disease. Many such drugs have shown early promise, only to fizzle in clinical trials. A growing number of Alzheimer’s researchers are now questioning whether amyloid is the best target for new medications.

A new paper — with postdoctoral scholar Sarah Ackley, PhD, as lead author and Maria Glymour, ScD, as senior author — offers a meta-analysis of all available evidence on amyloid-reducing strategies from past randomized controlled trials. Their findings suggest that it’s perhaps time for new ideas. The paper, published February 25 in The BMJ, re-examined evidence from 14 trials evaluating 8 drugs that measured changes in brain amyloid and cognition for people in the studies. Using a novel statistical method to evaluate trials of different drugs on the same scale, the paper found it was unlikely that amyloid reduction would improve cognition within the time-frame of the trials being conducted.

But what about the data from the most recent clinical trials? Recently, Eisai Pharmaceuticals and Biogen reported statistically significant evidence of cognitive benefit in one trial of an amyloid-reducing drug, aducanumab. Another trial of the same medication did not show benefits. How should these inconsistent results be interpreted? Meta-analysis provides a clearer picture.  When combining the aducanumab results with other evidence on amyloid-reducing drugs, we don’t see evidence of an overall benefit. Statistical significance thresholds suggest that 1 in 40 trials of a non-effective biological target will appear effective – or, as Ackley put it, “even a broken clock is right twice a day.” So, it’s possible aducanumab is more effective than other drugs targeting amyloid, but the recent results could also be chance findings.

Ackley and Glymour’s study also includes an online calculator that will allow researchers to add any subsequent clinical trial data to the meta-analysis as more data emerges. Still, it’s unlikely the overall picture for amyloid-targeting drugs will change. 

“Even the best-case scenario — including if a single successful trial is added to the meta-analysis — isn’t very compelling. Even with new evidence, our results indicate amyloid reduction is unlikely to substantially alter disease course within a reasonable time frame,” Ackley said.

By challenging the assumption behind existing Alzheimer’s medications, the paper may push the field to find new ways to treat the disease.