KL*VS Heterozygosity Reduces Brain Amyloid in Asymptomatic at Risk APOE*4 Carriers.

Abstract KLOTHO*VS heterozygosity (KL*VSHET+) was recently shown to be associated with reduced risk of Alzheimer’s disease (AD) in APOE*4 carriers. Additional studies suggest that KL*VSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across five independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KL*VSHET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE*4 status. KL*VSHET+ reduced the risk of amyloid positivity in APOE*4 carriers (OR=0.67 [0.52,0.88]; P=3.5x10-3), but not in APOE*4 non-carriers (OR=0.94 [0.73,1.21]; P=0.63). The combination of APOE*4 and KL*VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE*4 and AD are warranted.