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Lane RF, Raines SM, Steele JW, Ehrlich ME, Lah JA, Small SA, Tanzi RE, Attie AD, Gandy S. Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J Neurosci. 2010 Sep 29;30(39):13110-5. PubMed.
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It is intriguing that SorCS1 (see AlzGene) has gender differences in functional effects on Aβ production as well as in the Liang et al., 2009, linkage study. Of course, it makes sense in that it ties into the overall story that genetic differences that increase Aβ production increase risk. It would be nice to see particular genetic variants influencing Aβ production rather than the manipulations of the whole protein level, but that is where we are with SorLA and now with SorCS1.
The issues with both SorLa and now SorCS1, and in fact with nearly every genetic risk factor beyond ApoE, are that most seem tied to Aβ accumulation, the effect size of polymorphisms is low, and specific functional mutations or alleles are not very clear. Modest effect sizes for SNPs in these genes don't mean you won't have potentially important targets for lowering Aβ. However, therapeutic relevance may be limited by issues of specificity with the more basic downstream sorting machinery for proteins like SorCS1. The closer you get to the secretases, the better chance you have for specificity and good therapeutic targets. So I would place SorCS1 in the category of potentially relevant.
That said, over a lifetime, small differences in sorting rates from variants that modestly impact Aβ production rates may have dramatic long term impact. You can make the analogy to compound interest rates, where a quarter point or half point difference in interest seems trivial and doesn't make a significant difference in an 18 month investment portfolio (or clinical trial) but adds up over the decades to really make a difference. My view is that SorLA and SorCS1 and other candidate late-onset AD genes tied to Aβ accumulation are best thought of in the context of prevention. Can we find safe ways to influence them that shift the long-term Aβ balance sheet in our favor?
Liang X, Slifer M, Martin ER, Schnetz-Boutaud N, Bartlett J, Anderson B, Züchner S, Gwirtsman H, Gilbert JR, Pericak-Vance MA, Haines JL. Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10. Hum Mutat. 2009 Mar;30(3):463-71. PubMed.View all comments by Gregory Cole