KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

Klotho-VS heterozygosity (KL-VS het ) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VS het 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-VS het 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-VS het 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-VS het on tau-PET showed a tendency to be stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS het was related to better memory functions and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VS het carriers versus non-carriers. Together, our findings provide evidence for a protective role of KL-VS het against tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.