By Rich Haridy
August 19, 2020

A new study is questioning whether potential Alzheimer’s treatments previously found to be ineffective in human trials should be re-examined, after the discovery of a specific gene that can inhibit a therapy’s efficacy is only present in 75 percent of people.

The long-standing cholinergic hypothesis for Alzheimer’s disease suggests the cognitive decline associated with the disease is caused by the reduced synthesis of a neurotransmitter called acetylcholine. This neurotransmitter plays a fundamental role in learning and memory.

Some of the only pharmacological treatments currently available for Alzheimer’s work by increasing acetylcholine concentration, however, these drugs are infamously inconsistent, not working for a large number of patients. And, drug treatments more specifically targeting these cholinergic systems for Alzheimer’s, have consistently failed in human trials despite extraordinarily positive animal studies.

Over the last few years, researchers have been investigating a specific gene called CHRFAM7A. The gene is unique to humans, and not found in primates, or rodents often used in preclinical animal studies. Because this particular gene influences acetylcholine receptors in the brain, the researchers hypothesized it playing a role in the reason why acetylcholine-targeting treatments have been failing in human trials.

A study published last year in the journal Translational Psychiatry found that 75 percent of people carry this particular gene. The study also found the one in four people without this particular gene responded much better to pre-existing cholinergic treatments for Alzheimer’s.

“This uniquely human gene modifies the alpha 7 nicotinic receptor and as a consequence, drugs that are optimized in mice are insufficient for 75 percent of the population that has the active CHRFAM7A gene and the humanized receptor,” explains corresponding author on the new study, Kinga Szigeti.

This new study set out to specifically investigate what effect the CHRFAM7A gene could have on the efficacy of cholinergic treatments designed to treat Alzheimer’s disease but previously failed in human clinical trials.

“This system that we created models the 25 percent of patients who could respond to the cholinergic drugs that supposedly failed in clinical trials, and contrasts them with the 75 percent whom likely will need a different approach,” says Szigeti.

The proof-of-concept study only experimented with induced pluripotent stem cells in laboratory conditions. However, the evidence gathered in the study suggests these drugs could be quite effective in the 25 percent of patients that do not carry the CHRFAM7A gene.

“Our data indicate that drugs that target the nerve cells in which acetylcholine acts as a neurotransmitter, known as the cholinergic system, may benefit 25% of the individuals and now we can identify who they are,” says Szigeti. “For Alzheimer’s, if we can treat 25% of patients, that is 1.5 million people. That would be a major advance.”

The next step for the researchers will be to validate these findings by re-examining data from the failed Alzheimer’s clinical trials testing these cholinergic treatments. If the data suggests treatment efficacy is fundamentally related to an absence of the CHRFAM7A gene, then a new clinical trial could be necessary.

“It takes a simple blood test to determine a patient’s genotype, which will reveal whether or not a patient will respond to this class of drugs,” adds Szigeti.

The new study was published in the journal EBioMedicine.

Source: University at Buffalo