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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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  • Julia Neitzel

    (Ludwig-Maximilians-Universität LMU
    Erasmus University Medical Center
    Erasmus University Medical Center)

  • Nicolai Franzmeier

    (Ludwig-Maximilians-Universität LMU)

  • Anna Rubinski

    (Ludwig-Maximilians-Universität LMU)

  • Martin Dichgans

    (Ludwig-Maximilians-Universität LMU
    German Center for Neurodegenerative Diseases (DZNE)
    Munich Cluster for Systems Neurology (SyNergy))

  • Matthias Brendel

    (Ludwig-Maximilians-Universität LMU)

  • Rainer Malik

    (Ludwig-Maximilians-Universität LMU)

  • Michael Ewers

    (Ludwig-Maximilians-Universität LMU
    German Center for Neurodegenerative Diseases (DZNE))

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.

Suggested Citation

  • Julia Neitzel & Nicolai Franzmeier & Anna Rubinski & Martin Dichgans & Matthias Brendel & Rainer Malik & Michael Ewers, 2021. "KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23755-z
    DOI: 10.1038/s41467-021-23755-z
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