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

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

doi:10.1038/s41467-021-23755-z

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

Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

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

Original language	English
Article number	3825
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23755-z
State	Published - 1 Dec 2021
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-021-23755-z

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@article{8f03836c0fc14950ba3fadf694bcf88d,

title = "KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer{\textquoteright}s disease",

abstract = "Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer{\textquoteright}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.",

author = "{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative (ADNI)} and Julia Neitzel and Nicolai Franzmeier and Anna Rubinski and Martin Dichgans and Matthias Brendel and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Enchi Liu and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Charles DeCArli and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Susan Landau and Cairns, {Nigel J.} and Erin Householder and Reinwald, {Lisa Taylor} and Virginia Lee and Magdalena Korecka and Irina Rachinsky",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-23755-z",

language = "English",

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issn = "2041-1723",

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T1 - KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)

AU - Neitzel, Julia

AU - Franzmeier, Nicolai

AU - Rubinski, Anna

AU - Dichgans, Martin

AU - Brendel, Matthias

AU - Weiner, Michael

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Shaw, Leslie M.

AU - Liu, Enchi

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Fox, Nick

AU - Thompson, Paul

AU - Schuff, Norbert

AU - DeCArli, Charles

AU - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Vemuri, Prashanthi

AU - Jones, David

AU - Kantarci, Kejal

AU - Ward, Chad

AU - Koeppe, Robert A.

AU - Foster, Norm

AU - Reiman, Eric M.

AU - Chen, Kewei

AU - Mathis, Chet

AU - Landau, Susan

AU - Cairns, Nigel J.

AU - Householder, Erin

AU - Reinwald, Lisa Taylor

AU - Lee, Virginia

AU - Korecka, Magdalena

AU - Rachinsky, Irina

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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JO - Nature Communications

JF - Nature Communications

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M1 - 3825

ER -

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

Abstract

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