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Basic Science and Pathogenesis.

Mohsen Sharifi Tabar1, Dongyu Wang2, Gina M Peloso2

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Summary
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Genetic factors influence Alzheimer's disease (AD) timing. This study identified APOE as critical and novel loci like ROR1, ROR2, ADAMTS8, and SHISA6, suggesting distinct genetic influences on AD onset over time.

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Area of Science:

  • Genetics and Genomics
  • Neuroscience
  • Precision Medicine

Background:

  • Alzheimer's disease (AD) risk is influenced by complex genetic factors, with genome-wide association studies (GWAS) identifying several AD-associated loci.
  • While heritable factors play a role in AD onset timing, GWAS specifically focused on time-to-AD onset are limited.

Purpose of the Study:

  • To identify genetic variants associated with the time to Alzheimer's disease (AD) onset using whole genome sequencing (WGS) data.
  • To investigate the role of genetic factors in the timing of AD onset across diverse ancestral populations.

Main Methods:

  • Utilized data from the Alzheimer's Disease Sequencing Project (ADSP) and Trans-Omics for Precision Medicine (TOPMed) program, including over 14,000 individuals with time-to-AD and WGS data.
  • Employed ancestry-specific Cox proportional hazards models, adjusting for demographic and genetic factors, across Non-Hispanic White, Black, and Hispanic populations.
  • Analyzed variants with minor allele frequency (MAF) >1%.

Main Results:

  • The APOE region showed the strongest association with AD onset timing in both ADSP and TOPMed datasets.
  • Genome-wide significance was reached for variants mapped to ROR1, ROR2, ADAMTS8, and SHISA6, genes involved in neuronal development, synaptic function, and neuroplasticity.
  • Limited overlap was observed between time-to-AD GWAS results and traditional case-control GWAS, except for APOE.

Conclusions:

  • Preliminary findings confirm the critical role of APOE in AD onset timing and identify novel potential loci.
  • Distinct genetic factors may influence AD risk over time compared to overall AD risk.
  • Further meta-analysis, rare variant assessment, and multi-ancestral analyses are ongoing to expand findings.