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Basic Science and Pathogenesis.

Jean Augustinack1, Josué Llamas Rodríguez2, Smriti Chadha2

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Phosphorylated tau (p-tau) accumulates early in posterior entorhinal cortex (EC) subfields, indicating vulnerability before cognitive decline. Vessel density correlates with tau burden in these early Alzheimer's disease (AD) regions.

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Area of Science:

  • Neuroscience
  • Neuropathology
  • Neuroimaging

Background:

  • Healthy memory depends on the entorhinal-hippocampal circuit.
  • Alzheimer's disease (AD) phosphorylated tau (p-tau) appears late in the hippocampus, after memory impairment.
  • The entorhinal cortex (EC) is an early site of p-tau formation, preceding hippocampal involvement and cognitive decline.

Purpose of the Study:

  • To investigate p-tau accumulation in specific entorhinal cortex (EC) substructures.
  • To analyze the relationship between tau pathology, neuronal types, and neurovasculature in the EC.
  • To identify early pathological markers for Alzheimer's disease (AD) in the EC.

Main Methods:

  • Postmortem brain samples (n=18) were analyzed for p-tau using immunostaining.
  • The entorhinal cortex (EC) was divided into eight subfields for detailed tau burden assessment.
  • High-resolution postmortem MRI (n=12) was used to map intracortical vasculature in 3D.

Main Results:

  • Posterior EC subfields (ECs and ECL) showed selective vulnerability to tau pathology in preclinical AD stages.
  • A strong positive correlation was found between posterior EC tau burden and Braak staging.
  • Regions with higher tau burden exhibited greater density of intracortical vessels.

Conclusions:

  • Specific posterior EC subfields are vulnerable to tau pathology early in AD pathogenesis.
  • Tau accumulation and vascular density in the EC provide insights into early AD vulnerability.
  • Detailed mapping of tau pathology and vasculature aids in understanding the neurodegenerative environment.