Huang, Yen-Ning

Abstract Background Plasma biomarkers offer improved accessibility compared to established diagnostic modalities for Alzheimer's disease (AD). However, current plasma biomarker candidates have not been tested comprehensively in diverse populations, and represent only a fraction of pathways dysregulated in AD. This study seeks to address these knowledge gaps through untargeted plasma biomarker discovery in African Americans (AA), an underrepresented group in AD research despite having a higher risk of developing dementia compared to non‐Hispanic Whites (NHW). Method Untargeted proteomics were generated using the SomaScan 7k platform on plasma samples from AA study participants clinically diagnosed as AD dementia ( n = 181) or cognitively unimpaired (CU; n = 142). Machine learning was implemented to identify a set of plasma proteins to distinguish between AD dementia and CU. Predictive models were constructed by elastic net regression optimized with nested cross‐validation on 6,853 proteins and evaluated by receiver operating characteristic analysis. The generalizability of plasma protein predictors was evaluated in an external Alzheimer's Disease Research Center cohort of 369 NHW and AA study participants diagnosed as AD dementia or CU. Result Thirty‐six proteins were selected as predictors. Proteins selected by machine learning were enriched for processes previously associated with AD including synaptic dysfunction, inflammation, vascular dysfunction, and amyloid processing. The 36 plasma proteins alone achieved an area under the curve (AUC) of 0.94 to classify AD dementia in the discovery cohort, representing a 22% improvement over a model including age and sex. The 36 proteins were validated in an external cohort also achieving AUC=0.94, a 35% improvement over age and sex. Conclusion Biomarker discovery combining untargeted proteomics and machine learning identified a set of plasma proteins that could serve as a novel and highly accurate diagnostic plasma biomarker panel for AD. Work is underway to assess the association of the predictive panel with p ‐tau217, medical comorbidities, and social/structural determinants of health.

Abstract INTRODUCTION We investigated associations of plasma proteins with blood‐based amyloid/tau/neurodegeneration/inflammation (A/T/N/I) biomarkers for Alzheimer's disease (AD). METHODS Plasma proteomics and clinical data from the Indiana AD Research Center ( N = 498) were used. Association analysis of plasma proteins with blood A/T/N/I biomarkers as well as diagnosis was performed, followed by replication in an independent cohort ( N = 323), network analysis, pathway enrichment, and machine learning classification to identify proteins and pathways related to AD risk. RESULTS We identified 35 proteins associated with AD, 20 of which were replicated in the independent cohort. We identified 150, 448, and 219 proteins associated with T/N/I biomarkers, respectively, revealing biomarker‐specific pathways. Network analysis identified two modules associated with T/N/I biomarkers, preserved in cerebrospinal fluid (CSF), and their enriched pathways. The classification model of proteins effectively differentiated AD (area under the curve [AUC] = 0.930). CONCLUSION Our findings suggest dysregulated plasma proteins and pathways in AD, enhancing our understanding of molecular mechanisms and diagnostic strategies for AD. Highlights Plasma proteins were identified as being associated with Alzheimer's disease (AD) and plasma biomarkers. The identified proteins were replicated in both plasma and cerebrospinal fluid (CSF) proteomics. The identified proteins were associated with AD biomarker‐specific pathways. The identified proteins improved the performance of the AD classification. Protein network analysis identified network modules and their enriched pathways.

Abstract INTRODUCTION African American (AA) individuals are underrepresented in biomarker studies for Alzheimer's disease (AD). Biomarkers that reflect the heterogeneity of AD and achieve the greatest accuracy across populations are sorely needed. METHODS Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in AA participants with clinical diagnoses of AD dementia ( n = 181) and cognitively unimpaired (CU, n = 142). Machine learning was used to identify a set of plasma proteins that yielded the best classification accuracy. RESULTS A set of 36 proteins achieved an area under the curve (AUC) of 0.94 to classify AD dementia versus CU, a 16% improvement over age, sex, and apolipoprotein E ( APOE) . This finding was replicated in multiple plasma and brain datasets (AUCs 0.73–0.97). Our findings underscore the importance of matrisome and cerebrovascular dysfunction in AD pathophysiology. DISCUSSION This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning. Highlights Conducted large‐scale plasma proteomics in Alzheimer's disease (AD) versus cognitively unimpaired controls. Machine learning biomarker discovery was replicated in an independent cohort. Novel set of proteins distinguishes AD versus controls with high accuracy (area under the curve [AUC] = 0.94). Achieved reproducibility across multiple replication cohorts (AUC = 0.73–0.97). Network analyses implicates matrisome biology and cerebrovascular dysfunction.