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)

Neurology

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

32 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 (US)
Article number	3825
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23755-z
State	Published - Dec 1 2021

Funding

Data used in the preparation of this manuscript were obtained from the ADNI database (adni. loni.usc.edu). As such, the investigators within the ADNI study contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this paper. The study was funded by DAAD post-doc fellowship (to J. N.), grants from the Alzheimer Forschung Initiative (AFI, Grant 15035 to M. E.), Legerlotz Stiftung (to M. E.), LMUexcellent (to M. E.), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant for major research instrumentation (DFG, INST 409/193-1 FUGG; to M. D.); Hertie Foundation for Clinical Neurosciences (to N. F.), LMU Förderung Forschung Lehre (Reg. 1032 to N. F.), European Union’s Horizon 2020 research and innovation programme (grant agreement No. 666881 [SVDs@target] and 667375 [CoSTREAM]; to M. D.), the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and the CRC 1123 (B3) to M. D.). M. B. received speaker honoraria from GE healthcare and LMI and is an advisor of LMI. ADNI data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging, and Bioengineering, and through contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org).

ASJC Scopus subject areas

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

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10.1038/s41467-021-23755-z

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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 Mesulam, {Marek Marsel}",

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

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

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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 - Mesulam, Marek Marsel

PY - 2021/12/1

Y1 - 2021/12/1

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

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