DOI: 10.1002/alz.081608 ISSN: 1552-5260

Altered Endogenous Expression of Alzheimer’s Risk Genes impacts Neural Morphology in a Large Cohort of Healthy study Participants

Xavier Bledsoe, Rebecca L Sale, Phillip J Lin, Eric J Gamazon
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Dysregulation of white matter tracts (WMTs) in the brain is a common feature of Alzheimer’s Disease (AD) and is associated with declining cognitive function. Two neuroimaging measures, Fractional Anisotropy (FA) and isometric volume fraction (ISOVF) represent WM integrity through quantifying organization of axon bundles and changes in extracellular fluid within the fiber tracts (as occurs in inflammation or degeneration) respectively. Previous work examining the genetic basis of WMT changes in AD largely focused on SNP‐level associations. Here, we leverage transcriptome wide association studies (TWAS) and Mendelian randomization (MR) to interrogate the expression‐mediated influence of AD genes on WMT integrity.


We first perform a multi‐tissue TWAS for AD by applying JTI‐PrediXcan to summary statistics from the largest AD GWAS meta‐analysis (Bellenguez, 2022). This approach leverages tissue‐specific eQTL models trained on data from the Genotype‐Tissue Expression project and enriched via Joint Tissue imputation to identify associations between genetically regulated gene expression (GReX) and AD (Barbeira, 2018). We apply prediction performance thresholds and correct for multiple testing. We perform similar TWAS using JTI‐PrediXcan on neuroimaging data from 33,000 participants in the UK Biobank to identify tissue‐specific associations between GReX and WMTs (FA and ISOVF) (Smith, 2021). We integrate these studies to identify AD‐associated genes associated with changes in FA or ISOVF. We quantify the GReX causal effect on WMTs through the MR protocol, MR‐JTI, which assumes gene expression as the exposure (Zhou, 2020).


Our AD TWAS identifies 59 genes. 14 occur at the APOE locus and we replicate 2 additional genes prioritized in the initial GWAS. FUMA analysis of our gene set implicates the brain as the primary tissue of downregulation (Watanabe, 2017). Neuroimaging analysis of these genes highlights 5 WMTs and 2 genes. GReX of CR1 is causally associated with ISOVF of the right acoustic radiation and superior longitudinal fasciculus. GReX of INO80E is causally associated with FA of the left inferior longitudinal fasciculus and the bilateral superior thalamic radiations.


By integrating TWAS of AD and neuroimaging data, we identify multiple significant, tissue‐specific, causal associations between AD‐associated GReX and the integrity of key WMTs associated with cognitive function.

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