<i>KLOTHO</i> heterozygosity attenuates <i>APOE4</i>-related amyloid burden in preclinical AD.

Abstract

To examine whether the <i>KLOTHO</i> gene variant KL-VS attenuates <i>APOE4-</i>associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three 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 <i>APOE4</i> 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 <i>APOE4</i> 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 <i>APOE4</i> on Aβ was different among KL-VS heterozygotes compared to noncarriers. <i>APOE4</i> carriers exhibited greater Aβ burden than <i>APOE4</i>-negative participants. This effect was stronger in CSF (<i>t</i> = -5.12, <i>p</i> < 0.001) compared with PiB-PET (<i>t</i> = 3.93, <i>p</i> < 0.001). In the stratified analyses, this <i>APOE4</i> effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: <i>t</i> = -5.09, <i>p</i> < 0.001; PiB-PET: <i>t</i> = 3.77, <i>p</i> < 0 .001). In contrast, among KL-VS heterozygotes, <i>APOE4</i>-positive individuals did not exhibit higher Aβ burden than <i>APOE4</i>-negative individuals (CSF: <i>t</i> = -1.03, <i>p</i> = 0.308; PiB-PET: t = 0.92, <i>p</i> = 0.363). These differential <i>APOE4</i> effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of <i>APOE4-</i>associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against <i>APOE4-</i>linked pathways to disease onset in AD.