KLVS heterozygosity reduces brain amyloid in asymptomatic at- risk APOE4 carriers

KLOTHO*VS heterozygosity ( KL *VS HET+ ) was recently shown to be associated with reduced risk of Alzheimer’s disease (AD) in APOE *4 carriers. Additional studies suggest that KL *VS HET+ 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 5 independent studies, comprising 3581 pre-clinical participants ages 60–80, to investigate whether KL *VS HET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE *4 status. KL *VS HET+ reduced the risk of amyloid positivity in APOE *4 carriers (odds ratio = 0.67 [0.52–0.88]; p = 3.5 × 10 −3 ), but not in APOE *4 non-carriers (odds ratio = 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.