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

Julia Neitzel; Nicolai Franzmeier; Anna Rubinski; Martin Dichgans; Matthias Brendel; Rainer Malik; Michael Ewers; Alzheimer’s Disease Neuroimaging Initiative (ADNI); HyungSub Shim

doi:10.1038/s41467-021-23755-z

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

Journal article

Open access

Peer reviewed

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

Julia Neitzel, Nicolai Franzmeier, Anna Rubinski, Martin Dichgans, Matthias Brendel, Rainer Malik, Michael Ewers, Alzheimer’s Disease Neuroimaging Initiative (ADNI) and HyungSub Shim

Nature communications, Vol.12(1), pp.3825-3825

06/22/2021

DOI: 10.1038/s41467-021-23755-z

PMCID: PMC8219708

PMID: 34158479

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Abstract

Klotho-VS heterozygosity (KL-VS ) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VS 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-VS 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-VS 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-VS on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS 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-VS carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VS against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

Aged

Alzheimer Disease - genetics

Alzheimer Disease - metabolism

Amyloid beta-Peptides - metabolism

Apolipoproteins E - genetics

Apolipoproteins E - metabolism

Brain - diagnostic imaging

Brain - metabolism

Female

Gene Expression

Glucuronidase - genetics

Glucuronidase - metabolism

Heterozygote

Humans

Klotho Proteins

Male

Memory Disorders - genetics

Memory Disorders - metabolism

Middle Aged

Polymorphism, Single Nucleotide

Positron-Emission Tomography - methods

Protein Binding

tau Proteins - metabolism

Details

Title: Subtitle: KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease
Creators: Julia Neitzel - Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. j.neitzel@erasmusmc.nl
Nicolai Franzmeier - Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Anna Rubinski - Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Martin Dichgans - Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Matthias Brendel - Department of Nuclear Medicine, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Rainer Malik - Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
Michael Ewers - German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Michael.Ewers@med.uni-muenchen.de
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
HyungSub Shim - Neurology
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), pp.3825-3825
DOI: 10.1038/s41467-021-23755-z
PMID: 34158479
PMCID: PMC8219708
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: P30 AG066462 / NIA NIH HHS CIHR U01 AG024904 / NIA NIH HHS
Language: English
Date published: 06/22/2021
Academic Unit: Neurology; Psychiatry
Record Identifier: 9984302208402771

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