Integrated Genomic and Proteomic Drug Target Discovery for Vascular Dementia and Alzheimer’s Disease
Shufan Huo1, Santiago Clocchiatti-Tuozzo2, Jessica Magid-Bernstein3, Richa Sharma4, Srikant Rangaraju3, Lauren Sansing3, Kevin Sheth5, Cyprien Rivier1, Guido Falcone3
1Yale University, 2Yale University, Department of Neurology, 3Yale School of Medicine, 4Massachusetts General Hospital, Brigham, Harvard, 5Yale UniversityDivision of Neuro and Critical Care
Objective:
To utilize a comprehensive multi-omic approach to identify novel drug targets that mediate the genetic risk of vascular dementia (VaD) and Alzheimer’s disease (AD).
Background:
VaD and AD are major detriments of brain health with significant genetic risk components. Current prevention strategies focus on risk factor control but integrating genomic and proteomic data could uncover key molecular targets for more effective treatments based on genetic insights.
Design/Methods:
We analyzed genomic and proteomic data from 53,014 UK Biobank participants. Using genome-wide association data for both dementia forms, we deployed four analytical steps (all corrected for multiple testing): (1) linear regression between polygenic risk scores (PRS) and 2,923 standardized protein levels measured at baseline, adjusted for age, sex, and genetic principal components; (2) association between selected proteins and dementia; (3) Mendelian Randomization to assess causality for the proteins from (1+2); and (4) mediation to quantify the intermediary role of causal proteins in the PRS-dementia relationship.
Results:
Our analyses revealed several proteins that causally mediate the association between polygenic risk and dementia. In VaD, we discovered 3 mediating proteins involved in neuronal differentiation and signaling (PALM, NEFL, CEND1, 2-3% mediated effect). For AD, five proteins showed significant mediation, the strongest effect seen in APOE (lipid transport, 10% mediated effect) and MENT (chromatin regulation, 5% mediated effect) confirming their known roles in neurodegenerative processes. Other proteins (PVR, LGMN, ERBB3, MZB1) are involved in cell adhesion, immune response, protein degradation, and signal transduction.
Conclusions:
Our multi-omic approach successfully identified several novel proteins and pathways involved in VaD and AD, revealing key pathways and therapeutic targets. While some proteins (APOE, ERBB3) are addressed by developing or existing drugs, others lack direct pharmacological targeting, highlighting opportunities for drug discovery and validation in prevention and treatment of dementia.
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