Study shows how common genetic variants in black Americans increase risk of Alzheimer’s disease

Researchers at Columbia University have discovered how variants of the ABCA7 gene, common in black Americans, increase the risk of Alzheimer’s disease. The study is published in the journal Cellular genomics.

The variants accelerate neurodegeneration by reducing the amount of neuropeptide Y, a protein essential for maintaining brain synapses and the resilience of brain neurons.

“Our findings not only advance our understanding of Alzheimer’s disease, but they also open a new avenue for developing treatments that could halt or reverse the progression of the disease,” said study leader Caghan Kizil, Ph.D., associate professor of neurological sciences (in neurology and the Taub Institute for Alzheimer’s Disease and Aging Brain Research) at Columbia University Vagelos College of Physicians and Surgeons.

Variants in the ABCA7 gene were first associated with an increased risk of Alzheimer’s disease about a decade ago, but it is still unclear how these variants cause the disease to progress.

Variants in the ABCA7 gene have been linked to an increased risk of Alzheimer’s disease in many ethnic and racial groups, but they are particularly prominent among black Americans. Variants in the ABCA7 gene are more strongly linked to Alzheimer’s disease in black Americans than the well-known APOE4 gene, the most influential Alzheimer’s disease gene in white Americans.

Understanding the molecular basis of genetic risk factors like ABCA7 is essential for the development of new drugs.

Zebrafish as models for discovery

In this study, Kizil and his colleagues deleted one of the two copies of the gene in zebrafish neurons (mimicking the gene’s disruption in humans). Kizil’s zebrafish allow his team to gain insights into Alzheimer’s disease variants in a matter of weeks, rather than the months or years it takes with other animal models.

In zebrafish, the researchers found that loss of the ABCA7 copy decreased neuropeptide Y expression in all brain regions, but was most pronounced in the hippocampus, the brain’s memory center.

“This disruption of neuropeptide Y levels impaired neurogenesis and reduced synaptic density, two key factors in Alzheimer’s pathology,” Kizil explains.

In human cells, researchers have discovered the same process in neurons derived from pluripotent stem cells and found evidence that the protective neuropeptide Y pathway is compromised in the brains of people with Alzheimer’s disease.

Researchers were able to rescue synaptic integrity in zebrafish by restoring neuropeptide Y or other components of its pathway, highlighting a potential therapeutic target for Alzheimer’s disease.