Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease

Nat Med. 2020 Aug;26(8):1256-1263. doi: 10.1038/s41591-020-0938-9. Epub 2020 Jun 22.


Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.

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

  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / pathology
  • Female
  • Genetic Heterogeneity
  • Humans
  • Male
  • Middle Aged
  • Neurofibrillary Tangles / genetics
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Phosphorylation
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / pathology
  • Severity of Illness Index
  • tau Proteins / genetics*


  • tau Proteins