KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

Authors

Julia Neitzel, Klinikum der Universität München
Nicolai Franzmeier, Klinikum der Universität München
Anna Rubinski, Klinikum der Universität München
Martin Dichgans, Klinikum der Universität München
Matthias Brendel, Klinikum der Universität München
Michael Weiner, University of California, San Francisco
Paul Aisen, University of California, San Diego
Ronald Petersen, Mayo Clinic
Clifford R. Jack, Mayo Clinic
William Jagust, University of California, Berkeley
John Q. Trojanowki, University of Pennsylvania
Arthur W. Toga, USC
Laurel Beckett, University of California, Davis
Robert C. Green, Harvard Medical School
Andrew J. Saykin, Indiana University Bloomington
John Morris, Washington University in St. Louis
Leslie M. Shaw, University of Pennsylvania
Enchi Liu, Janssen Alzheimer Immunotherapy
Tom Montine, University of Washington
Ronald G. Thomas, University of California, San Diego
Michael Donohue, University of California, San Diego
Sarah Walter, University of California, San Diego
Devon Gessert, University of California, San Diego
Tamie Sather, University of California, San Diego
Gus Jiminez, University of California, San Diego
Danielle Harvey, University of California, Davis
Matthew Bernstein, Mayo Clinic
Nick Fox, University of London
Paul Thompson, Keck School of Medicine of USC
Norbert Schuff, University of California, San Francisco
Charles DeCArli, University of California, Davis
Bret Borowski, Mayo Clinic

Document Type

Article

Publication Date

12-1-2021

Journal

Nature Communications

Volume

12

Issue

1

URL with Digital Object Identifier

https://doi.org/10.1038/s41467-021-23755-z

Abstract

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.