Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models

Jingjing Zhu; Shuai Liu; Keenan A Walker; Hua Zhong; Dalia H Ghoneim; Zichen Zhang; Praveen Surendran; Sarah Fahle; Adam Butterworth; Md Ashad Alam; Hong-Wen Deng; Chong Wu; Lang Wu

doi:10.1186/s13195-023-01378-4

Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models

Alzheimers Res Ther. 2024 Jan 11;16(1):8. doi: 10.1186/s13195-023-01378-4.

Authors

Jingjing Zhu^#¹, Shuai Liu^#¹, Keenan A Walker², Hua Zhong¹, Dalia H Ghoneim¹, Zichen Zhang³, Praveen Surendran⁴, Sarah Fahle⁴, Adam Butterworth^{4

5}, Md Ashad Alam^{6

7}, Hong-Wen Deng⁶, Chong Wu⁸, Lang Wu⁹

Affiliations

¹ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA.
² Laboratory of Behavioral Neuroscience, National Institute On Aging, Intramural Research Program, Baltimore, MD, USA.
³ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Tulane Center for Biomedical Informatics and Genomics., Division of Biomedical Informatics and Genomics, Deming Department of Medicine, Tulane University, 1440 Canal Street, New Orleans, LA, 70112, USA.
⁷ Center for Outcomes Research, Ochsner Clinic Foundation, New Orleans, LA, 70121, USA.
⁸ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cwu18@mdanderson.org.
⁹ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA. lwu@cc.hawaii.edu.

^# Contributed equally.

Abstract

Background: Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.

Methods: We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent.

Results: We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment.

Conclusions: Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

Keywords: Alzheimer’s disease; Genetic instrument; Protein biomarker; Risk.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Biomarkers
Blood Proteins / genetics
Genome-Wide Association Study
Humans
Proteomics
Risk Factors

Substances

Blood Proteins
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding