alzheimer’s disease genes
The recent discovery of five additional genes associated with late-onset Alzheimer’s disease is much more significant and more interesting than I appreciated at the point of hearing about it. Besides opening the door for important future work, knowing this expanded set of genes, and their associated functions, allows for a cleaner picture of what’s going on with the disease. Five of the genes ten are involved in the immune system; four of the ten are involved in processes at the cell membrane; and three of the ten (including APOE) are involved in lipid processing. These functions are likely related to neurodegeneration and ABeta clearance.
Both papers start out with some rather heavy background, emphasizing complementary points. One says that a lot of people have Alzheimer’s disease, 13% of individuals aged 65 years and older, and 30-50% of individuals aged 80 years and older. The other says that it’s genetically complex and shows high heritability, up to 79%. Both briefly describe what was known in terms of associated genes, such as that APOE has a significant influence on susceptibility. A simplified point on APOE is that having 2 E4 alleles imparts between 10 and 30x risk of AD by 75 years of age, compared to those who not carrying any E4’s (so including the E2’s?). So what genes did these two recent studies find? The new ones are: ABCA7 (rs3764650); MS4A (rs610932 and rs670139, one in MS4A6A and other between MS4A4E and MS4A6A); CD2AP (rs9349407); CD33 (rs3826655 and rs3865444); EPHA1 (rs11767557). The known ones that they replicated are: CR1; CLU; BIN1; PICALM; APOE. I need to do more study on function, but want to list some basic things.
ABCA7 is believed to have a role in lipid homeostasis. It encodes ATP-binding cassette sub-family A member 7, one of the ABC transporters (its part of the ABC1 subfamily). ABC transporters move stuff across intra- and extra-cellular membranes. The genes in the MS4A cluster are probably part of a family of cell-surface proteins. MS4A2 encodes the Beta subunit of high affinity IgE receptors, but nothing else is known in terms of the function of the others. CD2AP encodes a scaffold adaptor protein that regulates the actin cytoskeleton, and associates with cortactin, which is involved in regulation of receptor-mediated endocytosis. CD33 (Siglec-3) is a member of the sialic-acid binding immunoglobulin-like lectins (Siglec) family, and is thought to “promote cell-cell interactions and regulate functions of cells in the innate and adaptive immune systems”. Members of the family mediate endocytosis through a mechanism independent of clathrin. EPHA1 encodes EPH receptor A1, the family of which has roles in cell and axon guidance, and synaptic development and plasticity. Its also been proposed to have roles in apoptosis and inflammation.