KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Abstract

© 2021 Elsevier Inc. 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.

RAS ID

36626

Document Type

Journal Article

Date of Publication

2021

Volume

101

Funding Information

Funding information : https://www.sciencedirect.com/science/article/pii/S0197458021000154?via%3Dihub

School

School of Medical and Health Sciences

Copyright

subscription content

Publisher

Elsevier

Comments

Belloy, M. E., Eger, S. J., Le Guen, Y., Napolioni, V., Deters, K. D., Yang, H. S., … Greicius, M. D. (2021). KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers. Neurobiology of Aging, 101, 123-129. https://doi.org/10.1016/j.neurobiolaging.2021.01.008

Link to Full Text

Share

 
COinS
 

Link to publisher version (DOI)

10.1016/j.neurobiolaging.2021.01.008