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Basic Science and Pathogenesis.

Lauren A Cruz1,2, Shiying Liu1,2, Kristy L Miskimen1,2

  • 1Case Western Reserve University, Cleveland, OH, USA.

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

T-cell receptor (TCR) diversity in blood is marginally linked to late-onset Alzheimer disease (LOAD) or mild cognitive impairment (MCI). Lower TCR diversity may indicate a higher risk for developing LOAD or MCI.

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Area of Science:

  • Immunology
  • Neuroscience
  • Genetics

Background:

  • Late-onset Alzheimer disease (LOAD) is a prevalent form of dementia in older adults.
  • Risk factors include age, sex, mild cognitive impairment (MCI), and APOE e4 genotype.
  • The adaptive immune system, particularly T-cells, plays a role in amyloid-β clearance, with potential blood-based immune profiles linked to LOAD.

Purpose of the Study:

  • To investigate T-cell receptor (TCR) sequence diversity in blood as a potential biomarker for LOAD.
  • To explore the association between TCR diversity and LOAD/MCI status using machine learning.

Main Methods:

  • Somatic TCR beta chain sequence diversity was analyzed using Adaptive Biotechnologies immunoSEQ.
  • Simpson's productive clonality and Morisita-Horn index were used to measure TCR diversity and repertoire similarity.
  • Fuzzy C-means clustering, an unsupervised machine learning approach, was applied to identify disease-specific patterns.

Main Results:

  • A significant trend of higher TCR sequence diversity was observed in non-LOAD participants compared to LOAD+MCI participants (p=0.027).
  • This association was not statistically significant after adjusting for age and sex.
  • Machine learning clustering showed moderate agreement with clinical diagnoses, improved by incorporating APOE genotypes.

Conclusions:

  • Decreased TCR diversity shows a marginal association with LOAD or MCI.
  • Future research will utilize machine learning on TCR sequences to identify disease-specific clonotypes and develop diagnostic models for LOAD.