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

• Published in: Neurobiology of aging Vol. 101; pp. 123 - 129
• Main Authors: Belloy, Michael E., Eger, Sarah J., Le Guen, Yann, Napolioni, Valerio, Deters, Kacie D., Yang, Hyun-Sik, Scelsi, Marzia A., Porter, Tenielle, James, Sarah-Naomi, Wong, Andrew, Schott, Jonathan M., Sperling, Reisa A., Laws, Simon M., Mormino, Elisabeth C., He, Zihuai, Han, Summer S., Altmann, Andre, Greicius, Michael D.
• Format: Journal Article
• Language: English
• Published: 01.05.2021
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2021.01.008

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 5 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 (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.