KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

Abstract

ObjectiveTo examine whether the KLOTHO gene variant KL-VS attenuates APOE4-Associated β-Amyloid (Aβ) accumulation in a late-middle-Aged cohort enriched with Alzheimer disease (AD) risk factors.MethodsThree hundred nine late-middle-Aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-Adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aβ was different among KL-VS heterozygotes compared to noncarriers.ResultsAPOE4 carriers exhibited greater Aβ burden than APOE4-negative participants. This effect was stronger in CSF (t =-5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: T =-5.09, p < 0.001; PiB-PET: T = 3.77, p < 0.001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: T =-1.03, p = 0.308; PiB-PET: T = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.ConclusionIn a cohort of at-risk late-middle-Aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-Associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.