Why Alzheimer’s drugs don't work -- Explained by new drug screening method

Researchers at the University of California, San Diego, devised a new way for screening therapeutics for Alzheimer's disease by studying disease mechanisms in human neurons. Their research elucidates why Alzheimer's medications have been ineffectual in curing or reversing the illness thus far, and identifies novel treatment targets.

The findings, which were published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, could pave the door for completely new therapeutic approaches to Alzheimer's disease.

The theory that amyloid plaques, which are generated by the buildup of amyloid-beta proteins in the brain, are what destroy neurons and cause Alzheimer's disease has long fueled drug development. As a result, a lot of research has gone into developing medications that can wipe up these plaques.

"However, this method has not resulted in a cure or a better quality of life for dementia sufferers. It has occasionally exacerbated the sickness "Shankar Subramaniam, a professor of bioengineering at the UC San Diego Jacobs School of Engineering, is the senior author.

Subramaniam and his partners devised a drug screening method that examines how disease processes, or endotypes, change in patients' neurons as a result of treatment to figure out why. Amyloid plaque development is the most well-studied Alzheimer's endotype. Other endotypes, which were discovered for the first time by Subramaniam and colleagues in a prior study, are also worth noting. De-differentiation of neurons to a "non-neuron" cell state, inhibition of neuronal genes, and loss of synaptic connections are just a few of them.

"This is a novel test for determining whether an Alzheimer's medicine is effective," Subramaniam explained. "The key is that we're using the endotypes we uncovered to figure out why present medications don't work. What endotypes do medications fix when they interact with human neurons, and what endotypes do they leave alone?"

This procedure is also unique in that it tests medications on actual patient cells. Subramaniam explained, "The power of this is that you can undertake precision treatment and have a good model system to investigate Alzheimer's."

Human induced pluripotent stem cells generated from patients with familial Alzheimer's disease, a genetic form of Alzheimer's, are transformed into neurons using this approach. The researchers employ medications to treat these neurons and then use next-generation sequencing to see how endotypes change before and after treatment. As a control experiment, the researchers run the chemical screen on neurons generated from healthy people.

The researchers tested two experimental Alzheimer's medications that were supposed to slow or stop the formation of amyloid plaques in this investigation. One was semagacestat, a medication candidate created by Eli Lilly that had failed late-stage clinical studies. The other was a medication candidate created by Steven Wagner, a professor of neurosciences at UC San Diego School of Medicine and Subramaniam's partner and co-author on the paper.

The medications only treat particular endotypes, such as the production of amyloid plaques, according to the researchers. The medications also help to reverse the dedifferentiation endotype by causing "non-neuron" cells to revert to neurons. However, as emphasised by Subramaniam, this change is not complete because the neurons still lack synaptic connections and hence are unable to communicate with one another.

Subramaniam remarked, "Now we have a prescription for what endotypes to target during drug screening." "What we're discovering is that preventing the production of amyloid plaques has no effect on the disease. It turns out that this endotype is too late because it's well downstream. Neurons that de-differentiate into non-neurons lose their synaptic connections, resulting in memory and cognition loss and, as a result, dementia."

"I'm really thrilled to employ these unique screening procedures for the Alzheimer's medications that my research is developing," Wagner remarked. "This is the first effort, in my experience in industry and now academia, to leverage numerous endotypes to overcome the failures of medications that target solely amyloid plaques."

The researchers will then use brain organoids to test their drug screening procedure. "We want to go a step further and evaluate medications on more realistic tissues rather than just neurons in a dish," Subramaniam added. The researchers will also concentrate on generating and assessing new Alzheimer's medication candidates using their technology.

Reference:

Andrew B. Caldwell, Qing Liu, Can Zhang, Gary P. Schroth, Douglas R. Galasko, Kevin D. Rynearson, Rudolph E. Tanzi, Shauna H. Yuan, Steven L. Wagner, Shankar Subramaniam. Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease. Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12553