Early Alzheimer's disease pathology in human cortex involves transient cell states

Area of Science:

• Neuroscience
• Genomics
• Pathology

Background:

• Alzheimer's disease (AD) research often relies on postmortem human tissues and model organisms.
• Understanding early cellular changes in living individuals is crucial for timely intervention.

Purpose of the Study:

• To create a single-nucleus atlas of cortical biopsies from living individuals with varying AD pathology.
• To identify cell states specific to early AD through cross-disease and cross-species analysis.

Main Methods:

• Generated a single-nucleus atlas from cortical biopsies of living individuals.
• Performed integrative analysis across diseases and species.
• Confirmed neuronal hyperactivity using acute slice physiology.

Main Results:

• Identified an 'early cortical amyloid response' characterized by a transitional hyperactive state in neurons before their loss.
• Observed expansion of microglia with neuroinflammatory processes as AD pathology increased.
• Found upregulation of genes related to beta-amyloid production and processing in oligodendrocytes and pyramidal neurons during early hyperactivity.

Conclusions:

• Early AD pathogenesis involves neuronal hyperactivity and neuroinflammation.
• These findings provide a framework for targeting early circuit dysfunction, neuroinflammation, and amyloid production in AD.
• The study highlights the potential of analyzing living patient biopsies for AD research.