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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 551 controls and patients across the AD continuum. KL-VS het  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-VS het  on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS het  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-VS het  carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VS het  against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.

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