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Basic Science and Pathogenesis.

Celeste Laureyssen1,2, Fahri Küçükali1,2, Jasper Van Dongen1,2

  • 1Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

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This study used deep phenotyping to find genetic links to Alzheimer's disease (AD) lesions, identifying novel risk genes beyond APOE. These findings help understand AD heterogeneity and guide future research into specific pathological features.

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Area of Science:

  • Neurogenetics
  • Alzheimer's Disease Research
  • Genomic Epidemiology

Background:

  • Alzheimer's disease (AD) is a complex, heterogeneous disorder with a significant genetic component.
  • Traditional genome-wide association studies (GWAS) are limited by phenotypic heterogeneity in clinical diagnoses.
  • This study addresses heterogeneity by conducting GWAS in a deeply phenotyped cohort with detailed neuropathological characterization.

Purpose of the Study:

  • To identify genetic associations with specific Alzheimer's disease-related lesions.
  • To investigate the genetic underpinnings of AD heterogeneity using neuropathological data.
  • To discover novel genetic loci contributing to sporadic AD risk and pathology.

Main Methods:

  • Genome-wide association studies (GWAS) were performed on 414 individuals from a European cohort.
  • Low-coverage whole-genome sequencing (lcWGS) was used for DNA analysis.
  • Association testing was conducted using PLINK2, with logistic or linear regression models applied based on phenotype type, adjusting for covariates.

Main Results:

  • Genome-wide significant and suggestive loci associated with AD heterogeneity were identified.
  • Novel loci, including variants in GYPE and upstream of ADAMTS16, showed associations with AD pathology scores and Braak staging.
  • Significant associations were found with co-morbid lesions, such as granulovacuolar degeneration (XAF1) and Hirano bodies (NRF1).

Conclusions:

  • Genome-wide significant associations with AD-related lesions were identified by controlling for phenotypic heterogeneity, despite sample size limitations.
  • Quantitative trait loci (QTL) analysis highlighted the molecular relevance of several loci, suggesting potential novel risk genes for AD.
  • Future research will focus on replication, meta-analysis, functional validation, and targeted resequencing to further understand implicated genetic regions.