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Basic Science and Pathogenesis.

Lisi Flores Aguilar1, Jesse R Pascual1, Halyma Nguyen1

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Individuals with Down syndrome and Alzheimer's disease show significant cerebrovascular changes, including blood-brain barrier breakdown. These findings highlight the need for caution when considering anti-amyloid immunotherapies for this population.

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Area of Science:

  • Neurology
  • Neuroscience
  • Vascular Biology

Background:

  • Adults with Down syndrome (DS) are entering Alzheimer's disease (AD) clinical trials for anti-amyloid immunotherapies.
  • Individuals with DS exhibit AD neuropathology and cerebrovascular disease, including cerebral amyloid angiopathy (CAA), by age 40.
  • This suggests a potentially higher risk of ARIA (amyloid-related imaging abnormalities) in this population.

Purpose of the Study:

  • To characterize cerebrovascular pathology in individuals with Down syndrome (DSAD).
  • To assess blood-brain barrier (BBB) integrity and vascular morphology in DSAD.
  • To inform the safe use of anti-amyloid immunotherapies in DSAD patients.

Main Methods:

  • Free-floating immunohistochemistry was used to analyze basement membrane, blood vessels, pericytes, and fibrin deposition in the occipital cortex.
  • Measurements included basement membrane coverage, vessel length and density, and pericyte and string vessel counts.
  • Fibrin deposition was scored, and statistical analyses included t-tests, Mann-Whitney, and Fisher's exact tests.

Main Results:

  • Adults with DSAD showed increased basement membrane coverage, vessel density, and length compared to controls.
  • An increased number of string vessels and pericytes were observed in DSAD.
  • Abundant fibrin deposition was found in DSAD brains, indicating a 3-fold increase compared to controls.

Conclusions:

  • Adults with DS at late stages of AD neuropathology exhibit vascular remodeling and BBB breakdown.
  • Careful evaluation is necessary before administering anti-amyloid beta immunotherapies to individuals with DS.
  • Cerebrovascular changes in DSAD warrant consideration for treatment strategies.