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

Background: 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. Method: 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. Result: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]