Klotho‐VS heterozygosity modifies amyloid‐dependent tau accumulation and memory impairment in Alzheimer’s disease

Abstract

Klotho-VS heterozygosity (KL-VShet ) is associated with reduced risk of developing Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, the key AD pathology driving cognitive decline, is unknown. Here, we tested the interaction between KL-VShet and beta-amyloid, the key driver of tau pathology, on PET-assessed neurofibrillary tau in elderly controls and patients across the AD continuum. In the ADNI cohort, we identified 144 KL-VShet carriers (55-90y, 53% women, 38% ApoE4+, 24% MCI) and 407 KL-VShet non-carriers (55-90y, 51% women, 37% ApoE4+, 29% MCI) with tau-sensitive ([18F]flortaucipir) and Aβ-sensitive ([18F]florbetapir or [18F]florbetaben) PET acquisitions as well as genetic and clinical information available. A subgroup of 200 participants (52 KL-VShet carriers) underwent a second tau-PET after 1.63 years on average. We assessed the KL-VShet x amyloid-PET interaction effect on tau-PET SUVR levels or annual change rates derived from an inferior temporal and global cortical ROI. Mediation analysis was used to determine whether KL-VShet was associated with better memory performance (ADNI-MEM), and whether this association was mediated by reduced tau-PET levels. All analyses were controlled for age, sex, diagnosis, education and ApoE4. We found a significant interaction effect indicating that KL-VShet carriers compared to non-carriers had lower inferior temporal (β=-0.12, P=0.009, effect size (Cohen's f)=0.112) and global (β=-0.13, P=0.008, effect size=0.114) tau-PET levels per centiloid (CL) unit increase in amyloid-PET (Fig 1a,b). Longitudinally assessed annual change rates of inferior temporal tau-PET were also lower in KL-VShet carriers per unit increase in baseline amyloid-PET (β =-0.22, P=0.039, effect size=0.148; Fig 1c,d). Post-hoc correlation analysis revealed that the KL-VShet effect on tau-PET was stronger in Klotho mRNA-expressing brain regions (Fig. 2). Importantly, KL-VShet was associated with better memory performance (β=0.13, p=0.040, effect size=0.104) in amyloid-positive participants and this association was significantly mediated by lower tau-PET levels. Our findings provide evidence for a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly individuals at risk of AD dementia. Hence, Klotho may be an attractive treatment target to slow the progression of AD.