Test Determines Why Alzheimer’s Drug Candidates Fail

Researchers at the University of California San Diego have developed a test to measure the effectiveness of drug candidates for Alzheimer’s disease and identified disease endotypes that help explain why strategies to date have been ineffective at curing or reversing the disease.

Drug development for Alzheimer’s has long been driven by the hypothesis that amyloid plaques—formed by the buildup of amyloid-beta proteins in the brain—are what kill neurons and cause Alzheimer’s. As a result, considerable research efforts have focused on designing drugs that clear out these plaques.

“But this approach has not led to a cure or improved dementia in patients. Sometimes it has made the disease worse,” says senior author Shankar Subramaniam, a professor of bioengineering at the UC San Diego Jacobs School of Engineering.

To understand why, Subramaniam and his collaborators developed a drug screening method that looks at what disease mechanisms change in patients’ neurons as a result of treatment. The most widely studied Alzheimer’s endotype is amyloid plaque formation. But there are other endotypes—reported for the first time by Subramaniam and colleagues in a previous study—that also warrant attention. These include de-differentiation of neurons to an earlier “non-neuron” cell state; suppression of neuronal genes; and loss of synaptic connections.

Subramaniam and his team human induced pluripotent stem cells derived from patients with familial Alzheimer’s disease and transformed them into neurons. They then treated these neurons with two experimental Alzheimer’s drugs designed to reduce or prevent growth of amyloid plaques. One was a drug candidate developed by Eli Lilly, called semagacestat, which had failed late-stage clinical trials. The other was a drug candidate developed by Subramaniam’s collaborator and co-author on the study, Steven Wagner, who is a professor of neurosciences at UC San Diego School of Medicine.

The researchers found that the drugs only fix some endotypes, such as the formation of amyloid plaques. The drugs also partly fix the de-differentiation endotype, by triggering “non-neuron” cells to transform back into neurons. However, this transformation is not complete, because the neurons still lack synaptic connections and therefore cannot communicate with each other.

 “What we are seeing is that fixing amyloid plaque formation does not reverse the disease in any way,” said Subramaniam.  “It turns out that this endotype is way downstream, so it’s too late. Once neurons de-differentiate into non-neurons, they lose their synaptic connections, which leads to loss of memory and cognition and as a consequence, dementia.”

Next, the researchers will evaluate their drug screening method on brain organoids. “We want to take this a step further to screen drugs on more realistic tissues, not just neurons in a dish,” said Subramaniam. The team will also work on developing new Alzheimer’s drug candidates and screening them with their method.

The findings were reported in a paper published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.