heterozygosity attenuates -related amyloid burden in preclinical AD.

Objective: To examine whether the gene variant KL-VS attenuates associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.

Methods: 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 status and underwent CSF sampling (n = 238) and/or C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether 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 on Aβ was different among KL-VS heterozygotes compared to noncarriers.

Results: carriers exhibited greater Aβ burden than -negative participants. This effect was stronger in CSF ( = -5.12, < 0.001) compared with PiB-PET ( = 3.93, < 0.001). In the stratified analyses, this effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: = -5.09, < 0.001; PiB-PET: = 3.77, < 0 .001). In contrast, among KL-VS heterozygotes, -positive individuals did not exhibit higher Aβ burden than -negative individuals (CSF: = -1.03, = 0.308; PiB-PET: t = 0.92, = 0.363). These differential effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.

Conclusion: In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against linked pathways to disease onset in AD.