Mayo Clinic researchers identify new genetic risk factor for late-onset Alzheimer's in African-Americans

Feb 28 2017

A Mayo Clinic research team has found a new gene mutation that may be a risk factor for late-onset Alzheimer's disease in African-Americans. This is the first time this gene has been implicated in the development of this disease in this population. Alzheimer's disease has been understudied in African-Americans, despite the fact that the disease is twice as prevalent in African-Americans, compared to Caucasians and other ethnic groups.

This likely pathogenic variant may be unique to the African-American population, the researchers say. It has not been found in Caucasians with Alzheimer's disease or in gene repositories from more than 60,000 subjects who are not African-Americans.
The findings, published in the February issue of the Journal of Alzheimer's Disease, represent the first comprehensive genetic screening in African-Americans for potentially pathogenic variants in known Alzheimer's genes.

Mayo Clinic Alzheimer's research seeks to paint a more complete genetic picture of genes that confer risk for Alzheimer's and genes that protect against that risk in different populations, says neurogeneticist Minerva Carrasquillo, Ph.D., who is the co-author.

"Currently, at least 5 million Americans are affected by Alzheimer's disease, and the rate of this devastating dementia is expected to rise dramatically in the coming decades," says Dr. Carrasquillo. "By uncovering genetic factors that modify the risk of Alzheimer's disease, there is the potential to identify druggable gene targets and genetic variants that could be used for early disease detection and prevention."

The research team's approach is to look at genetic factors known to be involved in early-onset Alzheimer's disease — dementia that occurs before 65 and sometimes in people as young as 30-40 years of age. Up to 5 percent of Alzheimer's disease has this early form, and a substantial number of these cases have been shown to be caused by genetic irregularities.

The investigators hypothesized that early-onset Alzheimer's disease genes may also be involved in late-onset Alzheimer's disease in African-Americans, although a comprehensive screen has not been done previously.

In this study, researchers looked for genetic mutations in three genes known to contribute to early-onset Alzheimer's disease. The three genes ─ APP, PSEN1 and PSEN2 ─ are involved in producing and cutting apart proteins as part of normal brain function. But mutations in these genes can result in increasing the amount of the amyloid beta peptide (Abeta) that leads to the amyloid plaques that build up in the brain of Alzheimer's patients. The rise in brain plaque quantity mirrors progression of Alzheimer's dementia.

While 200 early-onset Alzheimer's disease mutations in these three genes have been identified in Caucasians with Alzheimer's disease, only three have been found in African-Americans with Alzheimer's disease — one APP mutation in a single family and two PSEN1 mutations. Of the two PSEN1 mutations, one was within a single African-American family, and one was in a female early-onset Alzheimer's disease patient. Before this study, no PSEN2 mutations had been found in African-American patients.

In this study, the team sequenced the genome of 238 African-Americans participants. This group was divided between 131 patients with late-onset Alzheimer's disease and 107 control participants. Investigators found six variants within the early-onset Alzheimer's disease genes in the patients, but not in the control group. Researchers then looked for these six gene variants in a second independent group of 300 African-Americans participants (67 with late-onset Alzheimer's disease and 233 controls) and found that four of the variants were in the control group. That means two variants ─ one in a shorter form of PSEN1 and one in PSEN2 ─ may pose risk for late-onset Alzheimer's disease in African-Americans.

PSEN1 variants had been found before in African-Americans with the disease, but this discovery of a likely pathogenic PSEN2 gene variant is new in this population, says Dr. Carrasquillo. "And as far as we know, it has not been found in other populations with late onset Alzheimer's disease."

"This study opens the door to further analysis of this gene variant ─ both in African-Americans with Alzheimer's and in other populations," she says.
"These findings, which require replication, represent an important step in expanding genetic research in Alzheimer's disease to minority populations," says the study's senior investigator, neurogeneticist and neurologist Nilufer Ertekin-Taner, M.D., Ph.D.