KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers
Authors/Creators
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
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.
Document Type
Journal Article
Date of Publication
2021
Volume
101
Publication Title
Neurobiology of Aging
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
Copyright
subscription content
First Page
123
Last Page
129
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