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, for the Alzheimer's Disease Neuroimaging Initiative, Rainer Malik, M Ewers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Article number3825
JournalNature Communications
Issue number1
Publication statusPublished - 22 Jun 2021

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2021, The Author(s).


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