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Neitzel, Julia; Franzmeier, Nicolai; Rubinski, Anna; Dichgans, Martin ORCID logoORCID: https://orcid.org/0000-0002-0654-387X; Brendel, Matthias ORCID logoORCID: https://orcid.org/0000-0002-9247-2843; Malik, Rainer und Ewers, Michael (2021): KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. In: Nature Communications, Bd. 12, Nr. 1, 3825 [PDF, 1MB]

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.

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