NEW YORK (Reuters Health) - Genetic variations in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene may contribute to the development of late-onset Alzheimer’s disease, according to a report in the October 18th issue of PNAS Early Edition.
Based on previously reported linkages of late-onset Alzheimer’s disease to chromosome 12, Dr. Andrew Grupe from Celera Diagnostics, Alameda, California and colleagues genotyped 282 single-nucleotide polymorphisms in 1089 Alzheimer’s disease subjects and 1196 nondemented controls.
In the initial analysis, one marker in GAPD was strongly associated with late-onset Alzheimer’s disease after correcting for APOE4, gender, and age of onset, the authors report.
Three single-nucleotide polymorphisms in GAPD paralogs were significantly associated with Alzheimer’s disease, the report indicates. Two markers in GAPDS (or GAPD2) were significantly associated in patients with disease onset before 75 years of age, whereas one marker in the GAPD pseudogene (pGAPD) on chromosome 12 was associated with later age of onset (75 years or greater).
Multilocus genotyping showed significant associations with late-onset Alzheimer’s disease for the GAPD-GAPDS and GAPDS-pGAPD combinations, the researchers note, but not for the GAPD-pGAPD combination.
Moreover, the investigators report, there was a “consistent and strong trend in risk estimates across the three GAPDS genotypes, conditional on the CG-GG two-locus genotype in the other two genes,” the researchers write.
“Not only is GAPD a key enzyme in cellular energy production,” the authors explain, “but it also plays an important role in several other cellular processes, including neuronal apoptosis and neurodegenerative diseases, including Alzheimer’s disease. It is known to bind amyloid precursor protein as well as amyloid-beta.”
“Further research is required to ascertain the role of the variants showing association with Alzheimer’s disease in this study, not only at the molecular but also the cellular level,” the researchers conclude. “One prediction is that neuronal cells bearing the risk alleles are more susceptible to certain apoptotic stimuli.”
“We plan to analyze a much larger number of SNPs for possible associations with Alzheimer’s disease and to confirm the GAPD association in other Alzheimer’s sample sets,” Dr. Grupe told Reuters Health.
“Our results may help identify existing medications that are beneficial for the treatment of neurodegenerative diseases such as Alzheimer’s disease,” he continued. “In addition, we hypothesize that these genetic markers will be useful as treatment response markers in clinical trials of Alzheimer’s disease and other neurodegenerative diseases for drugs that act through GAPD.”
Source: Proc Natl Acad Sci USA Early Edition 2004.doi:10.1037/pnas.0403535101. [ Google search on this article ]
MeSH Headings:Age of OnsetCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
