Genetic Overlap Between Alzheimer`s, Immune-Mediated Diseases

By Larry Hand

NEW YORK - Genetic overlap exists between Alzheimer's disease (AD) and immune-mediated diseases, which suggests that immune system processes are part of AD pathogenesis and progression, according to an international team of researchers.

"This study represents the first step toward identifying biological targets related to immune function and inflammation that may be amenable to future therapeutic intervention in Alzheimer's disease," Dr. Jennifer Yokoyama, of the University of California, San Francisco, told Reuters Health by email.

"Our study shows that there are shared genetic risk factors for Alzheimer's disease and autoimmune diseases," she said. "This suggests that immune processes may directly contribute to Alzheimer's pathology and disease progression rather than emerge as a byproduct of the disease. This does not mean that people with autoimmune disease will necessarily develop Alzheimer's disease. Rather, this association suggests that shared biological pathways may underlie both autoimmune disease and Alzheimer's disease."

Dr. Yokoyama and colleagues conducted a genetic epidemiology study using data from genome-wide association studies from multiple research centers to search for genetic overlap between AD and Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis. The data covered more than 100,000 individuals.

They found eight single-nucleotide polymorphisms (SNPs) to be significantly associated with both immune-mediated diseases and AD.

One of the SNPs, with the closest gene being HLA-DRB5, specifically showed increased risk of both AD and psoriasis. Another, with the closest gene being IPMK, specifically showed an increased risk for AD and Crohn's disease. Those two SNPs showed the same direction of allelic effect between AD and immune-mediated diseases and were found to be associated with greater intracranial neurofibrillary tangles burden.

"These findings suggest that immune- and inflammation-associated genes, particularly the HLA locus and IPMK, likely influence AD pathogenesis and progression," the researchers write in an article online April 18 in JAMA Neurology.

"We think our study offers an important inroad into the Alzheimer's disease process and points to biological systems that might be amenable to therapeutic intervention," Dr. Yokoyama told Reuters Health. "The broader goal of our research is to work toward defining all of the myriad risk factors for Alzheimer's disease so that one day we can use this information in the clinic."

"It may be helpful for clinicians to be aware of potential links between autoimmune disease and cognition, because subtle declines in cognitive functioning may be early signs of an underlying neurodegenerative process," she added.

In an accompanying editorial, Dr. Huntington Potter of the Rocky Mountain Alzheimer's Disease Center, University of Colorado Anschutz Medical Center, Aurora, says the new study provides "a major intellectual and technological advance" in understanding the immune system's relationship to AD.

The paper describes two fundamental advances, he adds. "The first major advance is that we now have an established technological approach for the statistical comparison of risk factor genes, alleles, and SNPs between Alzheimer disease and any other disorder."

"The second major advance is that now immune-related disorders, specifically autoimmune disorders and the inflammation that accompanies them, have been genetically linked as a class to Alzheimer disease, which may suggest approaches to understanding important new steps in the Alzheimer disease pathogenic pathway. In turn, this may lead to new approaches to therapeutic intervention," Dr. Potter writes.

SOURCE: https://bit.ly/1SrfZCb and https://bit.ly/1XHji9v

JAMA Neurol 2016.

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