Repeat Coding in Gene Region Linked to Risk of Late-onset Alzheimer’s, Study Suggests

Longer sequence repeats in or near two genes may be linked to a higher risk of late-onset Alzheimer’s disease, a study reports.

The study “Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene” was published in the Journal of Neuropathy and Experimental Neurology.

Late-onset Alzheimer’s, or symptoms first evident after age 60, is highly heritable. However, previous research has failed to identify genetic variations (mutations) accounting for a significant proportion of the risk for this disorder.

In a study in elderly twins in Sweden, inheritance explained 79% of the risk, but common mutations accounted for only up to 50% of the variable clinical presentations.

One possible reason for this is that certain regions of the genome are harder to analyze than others. In particular, regions with a high number of sequence repetitions have historically been difficult to analyze. (Sequence repetitions are repeated units of coding in genes, the nucleotides A,T,G, and C that are the building blocks of DNA.)

Researchers at the Sanders-Brown Center on Aging at University of Kentucky used whole-exome sequencing to find new genetic variants associated with late-onset Alzheimer’s. This technique focuses on the small DNA bits (exons) that contain information to make proteins.

The team used two large databases, the Alzheimer’s Disease Genetic Consortium (ADGC) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Overall, this included genetic data on 5,142 people with Alzheimer’s and 4,889 people without the disease serving as controls.

All were of European ancestry. This leads to greater genetic similarity within the sample to limit the amount of confounding factors.

Results showed several mutations in exon 31 of the MUC6 gene that were associated with late-onset Alzheimer’s. However, the quality of the sequencing data for this region was low, which could be explained by its variable number tandem repeat regions, or VNTR regions.

In MUC6, VNTR regions are significantly longer and contain shorter repeats than in most of the human genome, which adds to the complexity of the study.

Researchers predicted that different numbers of repeats might explain the low quality of the genetic data, and that these differences could account for Alzheimer’s risk. They tested this using DNA taken from autopsy samples from 292 people with Alzheimer’s.

Those with longer VNTR regions had significantly more tangles made of an altered (phosphorylated) protein called tau in the brain, a hallmark change in Alzheimer’s patients. Specifically, this was found in the neocortex, a brain area involved in functions such as motor control, thought, and language. As such, this suggests that variations in this region may affect disease progression and cognitive function.

In contrast, the length of the VNTR region was not significantly associated with the amount of amyloid-beta, the main component of senile plaques in Alzheimer’s patients.

Researchers also found that the expression of another gene, called AP2A2, was lower in patients with longer than with shorter VNTR regions. The resulting protein was often found at the same spots as altered tau in people with late-onset Alzheimer’s.

“Together, these data indicate a genomic region with sequence variation relevant to neocortical … degeneration,” the researchers wrote.

The researchers propose that their study be seen as a first step in research into the mechanisms by which variations in the VNTR regions of MUC6 and near AP2A2 affect the brain.