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Area of Science:

  • Neuroscience
  • Genetics
  • Vascular Biology

Background:

  • Vascular dementia and Alzheimer's disease (AD) are increasingly recognized.
  • Blood-brain barrier (BBB) breakdown is an early biomarker for cognitive dysfunction, including early AD stages.
  • The apolipoprotein E4 (APOE4) variant accelerates BBB breakdown and pericyte degeneration.

Purpose of the Study:

  • To investigate if APOE4's cerebrovascular effects contribute to cognitive impairment.
  • To determine if BBB breakdown is associated with APOE4 genotype in specific brain regions.
  • To explore the relationship between BBB integrity, APOE4, and cognitive decline.

Main Methods:

  • Comparison of BBB integrity in APOE4 carriers versus non-carriers using brain imaging and cerebrospinal fluid (CSF) biomarkers.
  • Measurement of amyloid-beta and tau pathology via CSF and positron emission tomography (PET).
  • Assessment of BBB pericyte injury (soluble PDGFRβ) and BBB-degrading pathway (cyclophilin A-matrix metalloproteinase-9) in CSF.

Main Results:

  • Individuals with APOE4 show BBB breakdown in the hippocampus and medial temporal lobe, evident even in cognitively unimpaired carriers.
  • BBB breakdown severity correlates with cognitive impairment and is independent of amyloid-beta and tau pathology.
  • Elevated soluble PDGFRβ in CSF predicts future cognitive decline in APOE4 carriers, linked to increased BBB-degrading enzyme activity.

Conclusions:

  • Blood-brain barrier breakdown contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology.
  • BBB dysfunction is a key factor in cognitive impairment for APOE4 carriers.
  • Targeting BBB integrity may offer a therapeutic strategy for APOE4 carriers experiencing cognitive decline.