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KL-VS heterozygosity is associated with reduced tau accumulation and lower memory impairment in Alzheimer's disease

By Julia Neitzel, Nicolai Franzmeier, Anna Rubinski, Martin Dichgans, Matthias Brendel, Rainer Malik, Michael Ewers, Alzheimer's Disease Neuroimaging Initiative (ADNI)

Posted 31 Jul 2020
medRxiv DOI: 10.1101/2020.07.29.20164434

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 354 controls and patients within the AD continuum. KL-VShet showed lower cross-sectional increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This effect of KL-VShet on tau-PET showed a tendency to be stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions 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 for a protective role of KL-VShet against tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

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