Brain Somatic Mutations Observed in Alzheimer's Disease Associated With Aging and Dysregulation of Tau Phosphorylation

Nat Commun. 2019 Jul 12;10(1):3090. doi: 10.1038/s41467-019-11000-7.


The role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aging / genetics
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Animals
  • Cell Line, Tumor
  • Female
  • Gene Knockdown Techniques
  • Haploinsufficiency
  • Hippocampus / cytology
  • Hippocampus / pathology
  • Humans
  • Loss of Function Mutation
  • Male
  • Mice
  • Middle Aged
  • Mutation Rate
  • NIMA-Interacting Peptidylprolyl Isomerase / genetics*
  • NIMA-Interacting Peptidylprolyl Isomerase / metabolism
  • Neurons
  • Phosphorylation / genetics
  • Polymorphism, Single Nucleotide
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / pathology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Whole Exome Sequencing
  • tau Proteins / metabolism*


  • MAPT protein, human
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Recombinant Proteins
  • tau Proteins
  • PIN1 protein, human
  • Pin1 protein, mouse