ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodegeneration
Identifying Transcriptomic Signatures that Mediate the Causal Effect of Genotype on Alzheimer's Disease
Simran Kaur 1,2
Anna Tyler 1
Giovanna Durante 1,3
Gregory Cary 1
Gregory Carter 1
Matthew Mahoney 1
1. The Jackson Laboratory, Bar Harbor, United States
2. Department of Biomedical Engineering, Boston University, Boston, United States
3. Program in Quantitative Biomedical Sciences, Dartmouth College Geisel School of Medicine, Hanover, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
The combined effects of thousands of genetic polymorphisms account for Alzheimer's disease (AD) genetic risk. Most AD polymorphisms affect gene expression. Thus, the transcriptome, the set of all gene expression levels for every gene in the genome, is a major mediator between the genotype to phenotype. The purpose of this project is to use genotypes, transcriptomes, and clinical phenotypes to identify the transcriptomic signature that mediates the causal effect of genotype on AD. By utilizing high dimensional mediation analysis (HDMA) and the ROSMAP (Religious Orders Study/Memory and Aging Project) longitudinal cohort, we reduce the genotype, transcriptome, and phenotype data to single scores encoding genotype, transcriptome, and phenotype correlations, and produce a ranked gene list based on putative causal importance of each gene for AD. Analysis of the up-and down-regulated genes prevalent in AD through Gene Ontology and KEGG databases reveals up-regulated functions which include angiogenesis and immune responses while down-regulated functions of genes include synaptic activity. Utilizing Clue.io to identify candidate drugs to suppress AD-pathology reveals a plausible list of therapeutic candidates, including targeted genes and compounds such as SMAD3, TM7SF2, and ABCB1, which counteract the transcriptomic signature identified and may block the devastating effects of AD related to inflammatory responses, Aβ-induced toxicity, and neuronal death.
Summary
Keywords
Alzheimer's disease, biodomains, causal inference, drugrepositioning, ROSMAP, Transcriptome
Received
30 September 2025
Accepted
06 February 2026
Copyright
© 2026 Kaur, Tyler, Durante, Cary, Carter and Mahoney. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Matthew Mahoney
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.