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Basic Science and Pathogenesis.

Sathyaseelan Chakkarai1, Mohsen Sharifi Tabar2, Xueqiu Jian1

  • 1University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

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This study found new genetic loci interacting with environmental factors to influence Alzheimer's disease (AD) risk markers. Modifiable lifestyle factors significantly impact genetic predisposition, offering new prevention and treatment strategies for AD.

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Area of Science:

  • Neurogenetics
  • Environmental Health
  • Medical Imaging

Background:

  • Epidemiological studies link environmental exposures to Alzheimer's disease and related disorders (ADRD) risk.
  • The preclinical phase of ADRD is long, making molecular mechanisms of environmental disruption and brain impact poorly understood.
  • Investigating gene-environment interactions is complex due to defining environmental variables and study heterogeneity.

Purpose of the Study:

  • To identify genetic loci (variance quantitative trait loci or vQTLs) sensitive to environmental influences on brain structure.
  • To investigate how environmental factors mediate gene-environment interactions in preclinical ADRD markers.
  • To leverage UK Biobank data for comprehensive analysis of genomic, imaging, and risk factor profiles.

Main Methods:

  • Utilized UK Biobank data (N=45,275) to map vQTLs for hippocampal volume (HV), white matter hyperintensity (WMH), and diffusion MRI metrics (FA, MD).
  • Employed deviations in phenotypic variance to detect vQTLs with environmental sensitivity.
  • Applied linear mixed models to identify environmental exposures mediating vQTL associations.

Main Results:

  • Identified five novel genome-wide significant loci for WMH burden and suggestive loci for HV and FA.
  • Found that sedentary behavior and lifestyle factors (smoking, alcohol) mediated associations for loci at 2q12.3 (ST6GAL2), 10p11.22 (ZEB1), and 17p11.2 (EPN2) with WMH.
  • Discovered ZEB1 regulates gut microbiome species linked to inflammatory bowel diseases, and ST6GAL2 is an inflammatory biomarker associated with alcohol consumption; risk loci were downregulated in the spleen and enriched in kidney cell types.

Conclusions:

  • Identified novel genome-wide loci interacting with environmental factors and associated with preclinical MRI markers of Alzheimer's disease.
  • Highlighted the significant impact of modifiable lifestyle factors on genetic risk for ADRD.
  • Suggested potential preventive and therapeutic strategies based on identified gene-environment interactions and emphasized the need for replication in diverse cohorts.