The last US-approved Alzheimer’s drug—which was a new package of two existing drugs in a single pill—received the green light in 2003. In the nearly two decades since, there have been countless failures to develop any new treatment for the most common form of dementia. The most recent was in March, when Biogen and its partner Eisai announced the failure of a drug targeting the buildups of amyloid proteins in the brain, which are a hallmark of the disease.

The constant failure of clinical trials in Alzheimer’s disease is one of the main factors that has made future drug development for the condition so expensive. Late last year, researchers from the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas estimated that the total cost of developing any new Alzheimer’s drugs, including failures, is estimated to be $5.7 billion—twice the average cost of drug development. Their work, which was published (paywall) in Alzheimer’s and Dementia Translational Research and Clinical Interventions (a journal created by the nonprofit Alzheimer’s Association), estimated that it will take $38.4 billion to create a promising pipeline of drugs that can also tackle the disease using several different approaches.

Historically, clinical trials for Alzheimer’s drugs have started late in participants’ progression with the disease. Scientists know that buildups of amyloid proteins and another kind called tau can start to accumulate in the brain years or even decades before a person starts to experience symptoms of memory loss or trouble with cognition. Once symptoms start, however, it’s often too late: They irreversibly damage groups of neurons in a way that the brain cannot recover from. Although drugs may slow some of these participants’ symptoms, they can’t undo any of the damage from the disease.

Ideally, clinical trials would start sooner, before participants begin to show symptoms. The trouble is, it’s nearly impossible to identify these patients. The brain is a resilient organ; if it finds that some of the ways it used to carry out normal tasks, like remembering to-do lists or new acquaintances’ names, are compromised, it can rely on other neuron connections and regions to carry it out. It also has no pain receptors. People who will go on to develop the disease, therefore, have no idea that anything is wrong. Scientists are working on ways to identify biomarkers—other changes to proteins in the blood, cognition, or even the eye—to try to identify such individuals, but at the moment, none are ready for clinical use.

In addition to the difficulty of finding suitable participants for Alzheimer’s research, clinical trials take years because the condition progresses very slowly. The authors of the above paper estimate that it takes over 13 years to put a drug through all of the clinical trials required for approval from the US Food and Drug Administration. The Pharmaceutical Research and Manufacturers of America, a trade group that lobbies for pharmaceutical companies, estimates that this process takes about a decade (pdf) for other drugs on average.

Cancer drugs, on the other hand, have been found to take significantly fewer resources and less time than other kinds of drugs to develop. They have far shorter clinical trials where success is measured by increased survival rates, and often piggyback off existing therapies to make incremental improvements.