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

Neitzel, J.; Franzmeier, N.; Rubinski, A.; Dichgans, M.; Brendel, M.; Malik, R.; Ewers, M.; Alzheimer's Disease Neuroimaging Initiative (ADNI),

2020-07-31 neurology
10.1101/2020.07.29.20164434 medRxiv
Show abstract

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimers 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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