Two Alzheimer’s Risk Genes Linked to Brain Atrophy

Two genetic variants previously linked to Alzheimer’s disease have been more specifically tied to brain atrophy that is characteristic of the disease.

A newly reported study, led by Liana Apostolova, M.D., Barbara and Peer Baekgaard Professor of Alzheimer’s Disease Research at the Indiana University School of Medicine, also found that the proteins produced by the genes and circulating in the blood were associated with the brain atrophy and could be used in Alzheimer’s-related tests in the future.

The study is believed to be the first to directly link common variants of the genes — ABCA7 and MA4A6A — to atrophy in cortical and hippocampal regions of the brain, which are associated with memory and other key functions. It’s also believed to be the first to link the atrophy to protein levels in the blood produced by the genes.

“We also found that the levels of the protein products of these genes, circulating in the peripheral blood, were associated with the cortical and hippocampal atrophy. This finding suggests that those results of gene expression could become useful biomarker blood tests for Alzheimer’s disease,” Dr. Apostolova said.

The study was published in the advance online edition of the journal Neurobiology of Aging.

Alzheimer’s disease is a progressive illness that is the leading cause of dementia and the sixth leading cause of death in the United States, according to the Alzheimer’s Association. There is no cure for the disease and currently available treatments can slow, but cannot stop, the deterioration.

Although scientists have been linking a growing number of gene variants to the risk of developing Alzheimer’s disease, most of the associations have not identified the specific mechanisms that would increase the risk of developing the disease.

For the new study, the researchers identified the top nine genetic variants that have been associated with Alzheimer’s disease risk, not including the APOe4 gene that has long been linked to increased risk for several characteristics of Alzheimer’s disease.

The study is believed to be the first to directly link common variants of the genes -- ABCA7 and MA4A6A -- to atrophy in cortical and hippocampal regions of the brain, which are associated with memory and other key functions. It's also believed to be the first to link the atrophy to protein levels in the blood produced by the genes. Image is for illustrative purposes only.
The study is believed to be the first to directly link common variants of the genes — ABCA7 and MA4A6A — to atrophy in cortical and hippocampal regions of the brain, which are associated with memory and other key functions. It’s also believed to be the first to link the atrophy to protein levels in the blood produced by the genes. Image is for illustrative purposes only.

Using magnetic resonance imaging tools to measure brain size and genetic analysis, the researchers looked for associations between the genetic variants and atrophy in the cortical and hippocampal regions of the brain, which are established physical biomarkers of Alzheimer’s disease. The studies were conducted in 50 participants with no cognitive difficulties and 90 who had been diagnosed with mild cognitive impairment, a condition that is associated with increased risk of developing Alzheimer’s disease. All of the participants were 50 years or older.

Just two of the genetic variants — known as ABCA7 and MA4A6A — appeared to be associated with the changes in brain structure.

About this genetics research

In addition to Dr. Apostolova, researchers contributing to the study were Leslie M. Ramirez of the Drexel University College of Medicine, Giovanni Coppola, Naira Goukasian, Sona Hurtz, Eric Klein, Shai Porat, Renee Sears, and Benjamin Wang of UCLA, Kristy S. Hwang of the Oakland University William Beaumont School of Medicine, Jennifer A. Eastman of the Northwestern University Feinberg School of Medicine and Nouchee Vang of the University of Minnesota.

Funding: Funding from the following sources supported the research: National Institutes of Health grants R01 AG040770, K02 AG048240, P50 AG16570 and P30 AG010133; and the Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development.

Source: Eric Schoch – Indiana University
Image Source: The image is in the public domain
Original Research: Abstract for “Common Variants in ABCA7 and MSA46A are Associated with Cortical and Hippocampal Atrophy” by Leslie M. Ramirez, Naira Goukasian, Shai Porat, Kristy S. Hwang, Jennifer A. Eastman, Sona Hurtz, Benjamin Wang, Nouchee Vang, Renee Sears, Eric Klein, Giovanni Coppola, and Liana G. Apostolova in Neurobiology of Aging. Published online November 5 2015 doi:10.1016/j.neurobiolaging.2015.10.037


Abstract

Common Variants in ABCA7 and MSA46A are Associated with Cortical and Hippocampal Atrophy

The precise physiologic function of many of the recently discovered AD risk variants remains unknown. The downstream effects of genetic variants remain largely unexplored. We studied the relationship between the top 10 non-APOE genes with cortical and hippocampal atrophy as markers of neurodegeneration using 1.5T magnetic resonance imaging, 1-million SNP Illumina Human Omni-Quad array and Illumina Human BeadChip peripheral blood expression array data on 50 cognitively normal and 98 mild cognitive impairment subjects. After explicit matching of cortical and hippocampal morphology we computed in 3D the cortical thickness and hippocampal radial distance measures for each participant. Associations between the top 10 non-APOE GWAS hits and neurodegeneration were explored using linear regression. Map-wise statistical significance was determined with permutations using threshold of p<0.01. MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy. Exploratory MS4A6A and ABCA7 peripheral blood expression analyses revealed a similar pattern of associations with cortical neurodegeneration. To our knowledge this is the first report of the effect of ABCA7 and MS4A6A on neurodegeneration. "Common Variants in ABCA7 and MSA46A are Associated with Cortical and Hippocampal Atrophy" by Leslie M. Ramirez, Naira Goukasian, Shai Porat, Kristy S. Hwang, Jennifer A. Eastman, Sona Hurtz, Benjamin Wang, Nouchee Vang, Renee Sears, Eric Klein, Giovanni Coppola, and Liana G. Apostolova in Neurobiology of Aging. Published online November 5 2015 doi:10.1016/j.neurobiolaging.2015.10.037

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