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

Authors

Michael E. Belloy
Sarah J. Eger
Yann Le Guen
Valerio Napolioni
Kacie D. Deters
Hyun-Sik Yang
Marzia A. Scelsi
Tenielle Porter, Edith Cowan UniversityFollow
Sarah-Naomi James
Andrew Wong
Jonathan M. Schott
Reisa A. Sperling
Simon M. Laws, Edith Cowan UniversityFollow
Elisabeth C. Mormino
Zihuai He
Summer S. Han
Andre Altmann
Michael D. Greicius
A4 Study Team
Insight 46 Study Team
Australian Imaging Biomarkers and Lifestyle (AIBL) Study
Alzheimer's Disease Neuroimaging Initiative

Document Type

Journal Article

Publication Title

Neurobiology of Aging

Volume

101

First Page

123

Last Page

129

Publisher

Elsevier

School

School of Medical and Health Sciences

RAS ID

36626

Funders

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

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

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.

DOI

10.1016/j.neurobiolaging.2021.01.008

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