Neitzel, JuliaFranzmeier, NicolaiRubinski, AnnaDichgans, MartinBrendel, MatthiasAlzheimer’s Disease Neuroimaging Initiative (ADNI)Malik, RainerEwers, Michael2025-03-052025-03-052021-06-22Neitzel J, Franzmeier N, Rubinski A, et al. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat Commun. 2021;12(1):3825. Published 2021 Jun 22. doi:10.1038/s41467-021-23755-zhttps://hdl.handle.net/1805/46225Klotho-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.en-USAttribution 4.0 InternationalMolecular imagingHaplotypesDementiaAlzheimer's diseaseArticle