Trends in Alzheimer’s drug research

"Looking at the current drug pipeline, I think we are only a few years away."

By Howard Fillit

Developing drugs for Alzheimer’s disease presents many challenges. Only five drugs have been approved by the FDA for Alzheimer’s patients, and they only tackle symptoms. No drug available today can prevent or slow the progression of the disease. But three trends in Alzheimer’s drug research lead me to believe we are on the cusp of change.

Better Designed Trials

Clinical trials are the final stages of a drug’s development. There are fewer drugs in trials for Alzheimer’s than for other diseases that already have treatment options, and the drugs that do reach this critical point tend to fail. An analysis by Dr. Jeffrey Cummings at the Cleveland Clinic found that 99.6% of drugs in late-stage Alzheimer’s clinical trials failed. Pfizer’s announcement that it is closing its neuroscience division bore out the risk of these failures: companies will decide that the development costs are too high for drugs with too little chance of success.

The failure rate is sobering, but improved clinical trials will change it. In the Alzheimer’s Drug Discovery Foundation’s (ADDF) 2017 Clinical Trials Report, I noted that we can lessen the risk of failure by designing better trials. And drug developers are doing just that.

The goals are to weed out ineffective drugs earlier, sufficiently power trials to get useable data, and ensure patients in trials have the underlying pathology a drug is designed to target.  At the ADDF, we are working with investigators to build compelling clinical evidence of effectiveness using biomarkers in smaller, phase2 trials before proceeding to very expensive phase 3 testing. Merck and Biogen are using a positive beta-amyloid PET scan as part of their inclusion criteria for patients included in trials for anti-amyloid drugs. We expect this trend to grow as new patient recruitment methods and biomarkers advance.

New Biomarkers

In 2012, the beta-amyloid PET scan became the first diagnostic test approved for Alzheimer’s disease. It has been a breakthrough for clinical trials. Researchers found that up to a third of patients in Alzheimer’s drug trials did not have beta-amyloid plaques and thus, did not have Alzheimer’s. So trials may have failed not because a drug was ineffective, but because participants didn’t have the condition it was designed to treat.

Biomarkers are critical to the success of clinical trials. In addition to patient inclusion, they can be used to demonstrate target engagement of a drug, indicate disease progression, and measure the clinical effect of a drug in trials. More are needed, and they are in development.

Teams are working to validate PET ligands for tau, epigenetic targets, and microglia, some of which are already being used in clinical trials. Fluid biomarkers are also developing rapidly. Tests of cerebrospinal fluid are becoming more widely used, and several blood tests are in development. A team of scientists from Japan and Australia recently announced progress on a blood test for Alzheimer’s. Three more teams—at the Florey Institute, the University of Calgary, and Brigham & Women's Hospital—are also developing blood-based biomarkers for Alzheimer’s, with support from the ADDF.

Novel Targets

For many years, most drugs reaching late stage trials had a single target: misfolded beta-amyloid proteins that comprise plaques. But the pipeline is becoming diversified with drugs that target the biology of aging. We know that aging is the greatest risk factor for Alzheimer’s. It can result in a cascade of dysfunction in our brains involving inflammation, mitochondria, proteostasis, oxidation, cellular stress, and vascular and epigenetic changes.

Our 2017 Clinical Trials Report found that 30 of the 126 drugs in trials for Alzheimer’s are still targeting beta-amyloid, but novel targets are gaining ground. Twelve drugs focused on inflammation are in trials, including GC021109 developed by Gliacure. Another 14 targeting aspects of mitochondrial dysfunction and 11 focused on vascular targets have also made it to the clinic. And the first epigenetic drug developed for Alzheimer’s—ORY-2001 by Oryzon Genomics—is preparing for phase 2 trials.

As our understanding of the causes of Alzheimer’s advances, more targets will emerge. The ADDF has always supported a wide array of novel targets to treat Alzheimer’s that focus on aging biology. And more funders are embracing this approach.

Together, the three trends I have outlined will result in the first disease-modifying drug for Alzheimer’s. Looking at the current drug pipeline, I think we are only a few years away. And that success will accelerate these trends and lead to more approved drugs. Alzheimer’s, now a specter to be feared as we get older, will become a treatable condition.


This article originally appeared as a Research Insights piece. In Research Insights, top scientists present current research trends, and share them with peers on ResearchGate. Their articles aim to provide insight and inspire collaboration among researchers working in related areas.

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Featured image: plaques (blue) in a mouse model of Alzheimer's disease. CC BY-NC-ND 2.0 Zeiss Microscopy