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 and Michael Ewers ()
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Julia Neitzel: Ludwig-Maximilians-Universität LMU
Nicolai Franzmeier: Ludwig-Maximilians-Universität LMU
Anna Rubinski: Ludwig-Maximilians-Universität LMU
Martin Dichgans: Ludwig-Maximilians-Universität LMU
Matthias Brendel: Ludwig-Maximilians-Universität LMU
Rainer Malik: Ludwig-Maximilians-Universität LMU
Michael Ewers: Ludwig-Maximilians-Universität LMU

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23755-z

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