Deciphering the genetic interaction between klotho and APOE with novel mouse models

Apolipoprotein E4 (APOE4), a common variant of APOE, is a major genetic risk factor for LOAD, but APOE4 carriers do not always develop LOAD. Several large‐scale genetic studies have identified a common haplotype of the aging factor klotho that modify disease risk in APOE4 carriers. In humans, klotho harbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S) that define the klotho V/S (KL‐V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL‐F/C) haplotype, which is not. We sought to understand this genetic interaction using novel mouse models.