KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease

Nat Commun. 2021 Jun 22;12(1):3825. doi: 10.1038/s41467-021-23755-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Female
  • Gene Expression
  • Glucuronidase / genetics
  • Glucuronidase / metabolism*
  • Heterozygote
  • Humans
  • Klotho Proteins
  • Male
  • Memory Disorders / genetics
  • Memory Disorders / metabolism*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Positron-Emission Tomography / methods
  • Protein Binding
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • tau Proteins
  • Glucuronidase
  • Klotho Proteins