Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease
More Alzheimer's Genes, Pathways Found
New studies could lead to better diagnosis of Alzheimer's disease.
By John Gever, MedPage Today
Medically Reviewed byZalman S Agus, MD
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VANCOUVER — MONDAY, July 16, 2012 (MedPage Today) —Four additional genes associated with increased risk of Alzheimer's disease, as well as a surprising biological pathway that may be involved in the condition, were reported here.
Three of the four new genes have functions that make sense in the context of Alzheimer's disease but that had not been targets of previous research, while the fourth does not have a known product, according to Valentina Moskvina, PhD, of Cardiff University in Wales.
In a separate study at the university, an analysis of mutations previously associated with Alzheimer's disease, reported by Peter Holmans, PhD, suggested that a cellular process called endocytosis is affected by many of them. Some earlier studies had linked endocytosis — in which cells take in proteins or other molecules by engulfing them — to beta-amyloid protein trafficking, but it had not been high on the list of processes thought to account for Alzheimer's disease pathology.
Both Moskvina and Holmans are associated with the International Genomics of Alzheimer's Project (IGAP), a research consortium set up to mine the extensive genetics data gathered from several large cohorts of patients and controls, totalling more than 60,000 individuals. They reported the findings at the Alzheimer's Association International Conference during a platform session.
One of the project's leaders, Gerard Schellenberg, PhD, of the University of Pennylvania in Philadelphia, told attendees that variants in 11 genes, including theAPOEgene for apolipoprotein E, have previously been found to be associated with increased or decreased risk for Alzheimer's disease.
Except forAPOE, these genes were identified in genome-wide searches for single nucleotide polymorphisms (SNPs) associated with disease risk. In each case (again, withAPOEexcepted), the extra risk conferred by these SNPs was small — about 10 percent to 15 percent above the average risk.
These ten genes were found on the basis of single risk-conferring SNPs. But Moskvina said that it might also be possible to identify disease-associated genes by looking for multiple SNPs within a gene that are ass0ciated with increased or decreased risk.
If SNPs at 20 locations within a gene appear to affect disease risk, even though their individual associations are too weak to be noticed in a conventional SNP analysis, it's a signal that the gene is important in the disease, Moskvina explained.
She and her colleagues conducted such a "gene-wide" analysis — not to be confused with a genome-wide analysis — with IGAP data from about 17,000 Alzheimer's disease cases and 37,000 controls.
The study yielded four genes that contained SNPs of which at least one was significantly associated with higher or lower disease rates in Alzheimer cases versus controls at aPvalue of 10-7or lower. Such tinyPthresholds are standard in genomic studies to compensate for the large number of spurious associations that would arise by chance when millions of SNPs are analyzed.
The genes and their known products, according to Moskvina, were as follows:
- MTSS1L: Metastasis suppressor 1-like protein. Involved in endocytosis.
- SPI1: Spleen focus formung virus proviral integration oncogene. Involved in myeloid and B-lymphoid cell development.
- HBEGF: Heparin-binding EGF-like growth factor. Acts as a mitogen and possibly involved in macrophage-mediated cellular proliferation.
- LOC388553: unknown, may be noncoding.
The link to endocytosis reported by Moskvina foreshadowed the presentation by Holmans, who followed her to the podium. He reported on a so-called pathway analysis of several million SNPs for their connection to Alzheimer's disease.
Pathways, in this context, are groups of genes whose protein products have a similar or related function.
Holmans and colleagues filtered the SNPs into groups based on their proximity, the notion being that SNPs close together are probably within the same or adjacent genes, which in turn probably have functional relationships. These SNP groupings were then run through four databases with information on some 10,000 pathways.
The two most common pathways for Alzheimer-related genes involved cholinergic neurotransmission and negative regulation of endocytosis, Holmans said. The analysis also confirmed that pathways involving innate immunity and blood lipids were over-represented.
As a biostatistician, Holman said he didn't know what role endocytosis might play in Alzheimer's disease pathology. However, the pathway study suggested that it was not related toAPOE, because when the analysis excluded genes close toAPOEas well as other potentially confounding loci, the results remained the same.
Several previous laboratory studies have indicated that disruptions in endocytosis precede and perhaps facilitate beta-amyloid plaque formation.
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