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Basic Science and Pathogenesis.

Sonal Kumar1,2, Annat Haber3, Catrina Spruce2

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Genetic factors, not just age, influence Alzheimer's disease (AD) biomarkers in marmosets. This study identifies potential genetic contributions to neurodegeneration, offering insights into human AD genetics.

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Area of Science:

  • Neuroscience
  • Genetics
  • Primate Models

Background:

  • Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by genetic and environmental factors.
  • Genome-wide studies have identified AD-associated variants, but the evolving polygenic risk over time remains unclear.
  • Common marmosets offer a valuable nonhuman primate model for studying age-related neurodegeneration and AD pathology.

Purpose of the Study:

  • To investigate genetic associations with plasma biomarkers related to Alzheimer's disease in a cohort of common marmosets.
  • To explore the interplay between age, sex, and genetic factors in AD biomarker variation.
  • To identify potential genetic loci contributing to neurodegeneration in a nonhuman primate model.

Main Methods:

  • Whole genome sequencing of over 100 marmosets (wild-type and PSEN1 mutant carriers).
  • Measurement of AD-associated plasma biomarkers (total tau, NfL, GFAP, beta-amyloid peptides).
  • Linear mixed model analysis to assess genetic associations with individual and composite phenotypes, adjusting for kinship and sex.

Main Results:

  • Females exhibited stronger correlations between neurodegeneration biomarkers (tTau, NfL, GFAP) and beta-amyloid peptides compared to males.
  • A significant positive correlation between NfL and age was observed exclusively in male marmosets.
  • Genome-wide scans identified numerous significant and suggestive single nucleotide polymorphisms (SNPs) associated with AD biomarkers.

Conclusions:

  • Age alone does not fully explain variations in AD-relevant biomarkers in marmosets, indicating a substantial genetic influence.
  • Heritable associations discovered in marmosets can provide valuable genetic insights into human AD progression and biology.
  • Further investigation into the functional impacts of identified genetic loci is warranted.