Modeling the Genetic Interaction Between Klotho and APOE Alleles in Alzheimer's Disease

PROJECT SUMMARY
Understanding how combinations of genetic risk factors influence risk for late-onset Alzheimer’s disease (LOAD)
can lead to targeted strategies for therapeutic intervention. Apolipoprotein E4 (APOE4), a common variant of
APOE, is the single largest genetic risk factor for developing LOAD.APOE4 status is linked to increased
inflammation and higher β-amyloid burden in LOAD patients. Despite this increased genetic risk profile, APOE4
carriers do not always develop LOAD in the course of their lifetime. Several large-scale genetic studies have
identified a common haplotype of the aging factor klotho that modify age of onset and reduce amyloid plaque
deposition specifically in APOE4 carriers, suggesting that klotho variants can provide a protective effect against
the development of LOAD by counteracting the negative effects of APOE4. In humans, klotho harbors two
common missense variants (rs9536314, p.F352V; rs9527025, p.C370S). The combination of these two coding
variants 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 protective against LOAD. The overall objective of this proposal is to
determine the physiological processes altered by klotho as an APOE4-specific protective factor in LOAD using
a set of recently-created mouse models harboring combinations of relevant human variants in both klotho and
APOE. Our central hypothesis is that the protective KL-V/S haplotype will significantly delay age-dependent
inflammation and amyloid deposition while the reference KL-F/C haplotype will fail to attenuate these hallmark
LOAD pathologies. We will assess multiple LOAD-relevant outcomes to validate and characterize this klotho-
APOE genetic interaction with three specific aims: (1) Determine the effects of klotho haplotypes on age-related
frailty and klotho isoform levels in blood and CSF in mice; (2) Determine changes in LOAD hallmark pathologies
driven by the interaction between klotho and APOE alleles in mice; and (3) Identify molecular signatures shared
in human LOAD stratified by klotho haplotype and the novel klotho mouse models. The outcome of this work will
result in the characterization of new mouse models of human klotho haplotypes and identify the pathways which
are differentially affected by klotho variants in an APOE-dependent manner. This information will provide a
biological basis for the epistatic interaction observed in human genetic studies, thereby providing the necessary
functional information to guide potential treatments based on KL-V/S protection for APOE4 carriers.

Grant Number: 4RF1AG075701-02
NIH Institute/Center: NIH
Principal Investigator: Gregory Carter