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Basic Science and Pathogenesis.

Marina Nascimento Silva1, Augusto Afonso Guerra-Júnior1

  • 1Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

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|December 24, 2025
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Summary

Individuals with Down syndrome (DS) have an increased risk of Alzheimer's disease (AD). This study identified 11 genes, including DYRK1A, involved in AD pathophysiology, offering potential therapeutic targets for both DS and the general population.

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Area of Science:

  • Genetics
  • Neurodegenerative Diseases
  • Molecular Biology

Background:

  • Down syndrome (DS) is characterized by trisomy 21, increasing Alzheimer's disease (AD) risk.
  • Overexpression of genes like amyloid precursor protein (APP) on chromosome 21 contributes to AD.
  • Understanding genetic links is crucial for developing diagnostics and therapeutics for AD in DS.

Purpose of the Study:

  • Investigate candidate genes for AD diagnosis and treatment in individuals with Down syndrome.
  • Explore the therapeutic potential of identified genes using Horizon Scanning in health technology assessment (HTA).

Main Methods:

  • Systematic review of Medline and Embase databases.
  • Selection of 6 relevant articles from 370 retrieved for final analysis.
  • Identification of genes implicated in AD pathophysiology in DS.

Main Results:

  • Eleven genes beyond APP were identified, linked to APP processing, tau modification, neuroinflammation, oxidative stress, and beta-amyloid clearance.
  • DYRK1A and SYNJ1 on chromosome 21 are implicated in APP processing and neuroinflammation.
  • DYRK1A overexpression is associated with tau hyperphosphorylation and beta-amyloid accumulation.

Conclusions:

  • Identified genes hold significant therapeutic potential for AD in DS.
  • DYRK1A inhibitors show promise in preclinical studies for reducing cognitive decline.
  • SYNJ1, SOD1, and RCAN1 are potential early diagnostic markers for AD.