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Klotho‐VS heterozygosity modifies amyloid‐dependent tau accumulation and memory impairment in Alzheimer’s disease
Author(s) -
Neitzel Julia,
Franzmeier Nicolai,
Rubinski Anna,
Dichgans Martin,
Brendel Matthias,
Malik Rainer,
Ewers Michael
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.051343
Subject(s) - tau pathology , standardized uptake value , oncology , psychology , medicine , alzheimer's disease neuroimaging initiative , amyloid (mycology) , alzheimer's disease , pathology , disease , endocrinology , positron emission tomography , neuroscience
Background Klotho‐VS heterozygosity (KL‐VS het ) is associated with reduced risk of developing Alzheimer’s disease (AD). However, whether KL‐VS het is associated with lower levels of pathologic tau, the key AD pathology driving cognitive decline, is unknown. Here, we tested the interaction between KL‐VS het 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‐VS het 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‐VS het 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‐VS het effect on tau‐PET was stronger in Klotho mRNA‐expressing brain regions (Fig. 2). Importantly, KL‐VS het 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‐VS het 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.