The Clu‐rs2279590_h2kb variant increases axonal and neuritic damage in 5xFAD mice

Genome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer's disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The rs2279590 SNP risk allele is located within a putative enhancer element in intron 7 of CLU. Indeed, deletion of a 115bp region including this SNP reduces expression of CLU and neighboring genes (EPHX2 and PTK2B) on Chromosome 8. The region surrounding rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.