Clusterin is a highly conserved glycoprotein that functions primarily as an extracellular chaperone. Multiple large genome-wide association studies (GWAS) have uncovered clusterin variants that strongly associate with late-onset Alzheimer’s disease, earning clusterin a spot on AlzGene’s top 10 risk genes.
Clusterin levels are elevated in the AD brain, but how the protein affects AD pathogenesis is unknown. One idea holds that pathogenic clusterin variants weaken the brain’s ability to respond to stressors, another that they work through reduced expression of clusterin. Prevailing hypotheses revolve around clusterin’s ability to bind Aβ peptides and thereby influence their aggregation, deposition, and/or clearance, but the underlying mechanism(s) remain to be delineated. Functional studies are starting to associate clusterin variants with neurological phenotypes. Clusterin is detectable in blood and cerebrospinal fluid, but thus far it has not proven useful as a biomarker.
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