Researchers have identified a gene that appears to increase a person's risk of developing late-onset Alzheimer disease (LOAD). MTHFD1L is on chromosome six and was identified in a genome-wide association study (GWAS).
Details are published September 23 in PLoS Genetics in a paper titled “Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities.” The collaborative team of researchers was led by Margaret A. Pericak-Vance, Ph.D., director of the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, Joseph D. Buxbaum, Ph.D., department of psychiatry, Mount Sinai School of Medicine, and Jonathan L. Haines, Ph.D., Vanderbilt Center for Human Genetics Research.
They combined data on 483,399 SNPs from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls. Associations exceeding the experiment-wide significance threshold were replicated in an additional 1,338 cases and 2,003 controls.
The SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L was significantly associated with LOAD, according to the scientists. They report that individuals with the variation may be nearly twice as likely to develop the disease as people without the variation.
MTHFD1L encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein. It is involved in the tetrahydrofolate synthesis pathway. The investigators also suggest that MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways.
"Identifying this gene is important because the gene is known to be involved in influencing the body's levels of homocysteine, and high levels of homocysteine are a strong risk factor for late-onset Alzheimer disease," remarks Dr. Pericak-Vance. "In addition, variations of the MTHFD1L gene have been reported to possibly increase the risk of coronary artery disease. Since the function of blood vessels in the brain may affect Alzheimer disease, this finding may help us understand how homocysteine levels and blood-vessel function in the brain affect Alzheimer disease."
Dr. Buxbaum says, "This finding gives us unique insight into possible interactions between genetic and environmental risk factors that contribute to AD. We know of environmental and lifestyle factors that can impact homocysteine levels, and it will be important to understand whether variations of the MTHFD1L gene can modulate these effects."