Abstract Details

Title Integrated Genomic and Proteomic Drug Target Discovery for Vascular Dementia and Alzheimer’s Disease

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-015

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.

Authors/Disclosures
Shufan Huo, MD, PhD (Yale University) PRESENTER	Dr. Huo has nothing to disclose.
Santiago Clocchiatti-Tuozzo (Yale University, Department of Neurology)	Mr. Clocchiatti-Tuozzo has nothing to disclose.
Jessica Magid-Bernstein, MD, PhD (Yale School of Medicine)	Dr. Magid-Bernstein has nothing to disclose.
Richa Sharma, MD (Massachusetts General Hospital, Brigham, Harvard)	Dr. Sharma has received research support from NIH. Dr. Sharma has received intellectual property interests from a discovery or technology relating to health care.
Srikant Rangaraju, MBBS (Emory University, Atlanta)	Dr. Rangaraju has nothing to disclose.
Lauren H. Sansing, MD	Dr. Sansing has nothing to disclose.
Kevin N. Sheth, MD, FAAN (Yale UniversityDivision of Neuro and Critical Care)	Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Cyprien Rivier, MD (Yale University)	Dr. Rivier has nothing to disclose.
Guido J. Falcone, MD (Yale School of Medicine)	The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.

��ɫ��

��ɫ��