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Basic Science and Pathogenesis.

Lisi Flores Aguilar1, Sierra Wright1, Jillian V Berry2

  • 1University of California, Irvine, Irvine, CA, USA.

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|December 23, 2025
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Summary
This summary is machine-generated.

Approximately 14% of individuals with Down syndrome (DS) over 40 years old showed resilience to Alzheimer's disease (AD) dementia, despite significant neuropathological changes. This suggests a potential protective mechanism against cognitive decline in this population.

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Area of Science:

  • Neurology
  • Genetics
  • Pathology

Background:

  • Individuals with Down syndrome (DS) have a significantly increased genetic risk for Alzheimer's disease (AD), with most exhibiting AD neuropathology by age 40 and dementia by their early 50s.
  • Despite high AD neuropathology, some individuals with DS do not develop dementia, indicating potential resilience factors.
  • Understanding this resilience is crucial for developing targeted therapies for AD in both DS and the general population.

Purpose of the Study:

  • To determine the proportion of individuals with Down syndrome who are resilient to Alzheimer's disease dementia.
  • To investigate the neuropathological characteristics of individuals with DS who exhibit resilience to AD dementia.

Main Methods:

  • A cross-sectional autopsy cohort study was conducted using data from 67 individuals with DS (ages 37-60) from the University of California, Irvine ADRC.
  • Neuropathology data, including AD markers and co-pathologies, were analyzed.
  • Dementia status was determined by an expert consensus panel based on clinical and cognitive data.

Main Results:

  • Out of 67 individuals with DS, nine (approximately 13.4%) did not have dementia despite intermediate to high AD neuropathological changes (Braak stage III-VI, Thal phase 3-5).
  • The remaining individuals in the cohort had AD dementia or possible AD dementia.
  • Cerebral amyloid angiopathy was the most common co-pathology (55%) among those without dementia.

Conclusions:

  • Approximately 14% of individuals with Down syndrome over 40 in the study cohort demonstrated resilience to Alzheimer's disease dementia.
  • These resilient individuals had significant AD neuropathological changes, suggesting underlying protective mechanisms.
  • Further research into these mechanisms could offer new therapeutic targets for Alzheimer's disease.