[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease

Nat Commun. 2022 Jul 19;13(1):4171. doi: 10.1038/s41467-022-30653-5.


Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.

Publication types

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

MeSH terms

  • Adamantane / analogs & derivatives
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / genetics
  • Cognitive Dysfunction* / metabolism
  • Histone Deacetylase 1* / metabolism
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids
  • Positron-Emission Tomography / methods
  • Rats
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Hydroxamic Acids
  • tau Proteins
  • martinostat
  • HDAC1 protein, human
  • Hdac1 protein, rat
  • Histone Deacetylase 1
  • Histone Deacetylases
  • Adamantane