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.
Highlights
Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD)
We demonstrate that elderly KL-VShet carriers with elevated Aβ burden, i.e., the earliest primary AD pathology, exhibited lower tau-positron emission tomography (PET) levels and tau-PET annual change rates when compared to those in KL-VShetnoncarriers
Our findings do not implicate a causative mechanism of Klotho in AD, we provide evidence for a potential protective role of KL-VShet against Aβ-dependent tau pathology that is the key AD brain alteration linked to cognitive impairment
Summary
Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). KL-VShet occurs in about 20–25% of the population[5] and is associated with higher cognitive performance across the adult life span[5,7,8,9], larger frontotemporal gray matter volume in cognitively normal individuals[8], and lower mortality[6,10] Together, these results suggest a crucial role of Klotho in the maintenance of cognitive abilities and brain integrity during aging. Studies in mouse models of Aβ and accelerated aging reported that enhancing KL expression was associated with reduced Aβ burden and phosphorylated tau[11,30], conflicting results were reported as well[31] These mouse models fail to develop neurofibrillary tangles in the presence of Aβ and only incompletely recapitulate AD-specific tau pathology in humans
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