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

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-beta 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-beta and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-beta, 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-beta PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-beta 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-beta 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.

Automated summary

Alzheimer's disease is characterized by the accumulation of amyloid-beta and tau proteins in the brain. Epigenetic dysregulation has been found to play a role in the interaction between these protein abnormalities, neurodegeneration, and cognitive impairment.