New insights into a specific gene variant may help explain why some Alzheimer’s drugs work for certain people but fail for others. The findings suggest that a more personalized approach to drug testing may be necessary.

Earlier this year, a study led by Dr. Kinga Szigeti, Ph.D., director of the Alzheimer’s Disease and Memory Disorders Center at the University at Buffalo, New York, identified a key gene that may explain why some Alzheimer’s drugs showed promise in animal models but failed in human trials. The gene, called CHRFAM7A, is unique to humans, although only about 75% of people have it. It is known as a fusion gene, meaning it combines a gene that encodes a receptor for the neurotransmitter acetylcholine with a type of enzyme called a kinase.

Acetylcholine plays a critical role in memory and learning, and researchers have long associated it with the development of Alzheimer’s disease. The CHRFAM7A fusion gene encodes the “alpha-7 nicotinic acetylcholine receptor.” However, because this gene exists only in humans, drugs designed to target the alpha-7 receptor have been successful in preclinical animal models but not in human trials.

Dr. Szigeti’s earlier research showed that CHRFAM7A has a modulatory effect on the uptake of the protein beta-amyloid, a hallmark of Alzheimer’s disease. However, that study was conducted using tissue cultures. In the more recent study, Dr. Szigeti and her team investigated how this gene affects drug effectiveness in humans. The researchers presented their findings at the Alzheimer’s Association International Conference held in Los Angeles, California.

Dr. Szigeti explains that the CHRFAM7A gene exists in two variants: one functional version and another that is not translated into a protein. This divides the population into roughly a 1-to-3 ratio between non-carriers and carriers. She also notes that three out of four currently available Alzheimer’s drugs target all acetylcholine receptors. However, drugs designed specifically to target the alpha-7 acetylcholine receptor have so far failed in human trials.

Because this human fusion gene was not present in the animal models and screening systems used to identify these drugs, about 75% of Alzheimer’s patients who carry the gene are less likely to benefit from them. According to Dr. Szigeti, this may explain the “translational gap” between successful animal studies and unsuccessful human trials.

To investigate further, the researchers compared the effects of cholinesterase inhibitors in patients who either carried or did not carry the gene. The team used data from a 10-year cohort study conducted by the Texas Alzheimer’s Research and Care Consortium, which involved 345 people living with Alzheimer’s disease.

The results showed that people who do not have the CHRFAM7A gene respond better to currently available drugs. Dr. Szigeti states that their work confirms the alpha-7 receptor as a very important target for treating Alzheimer’s disease, but emphasizes that the correct model—specifically a human model—must be used when testing new drugs.

In practical terms, this means that a drug may work well for about 25% of people with Alzheimer’s but fail in the remaining 75%, or vice versa. These findings highlight the importance of a more personalized approach to both treatment and drug development for Alzheimer’s disease.

The researchers also stress that their study is only a proof of concept and has certain limitations. They note that randomized, double-blind clinical trials will be needed to confirm these results.