Proteomic Analysis Resolves Distinct Molecular Signatures in Alzheimer’s Disease Brain Across Diverse Racial Groups
Authors: Seifar Fatemeh , Fox Edward J , Shantaraman Anantharaman , Liu Yue , Modeste Erica S. , Duong Duc M , Yin Luming , Gearing Marla , Lah James J. , Reddy Joseph S. , Allen Mariet , Quicksall Zachary , Heath Laura M , Scanlan Jo , Wang Erming , Wang Minghui , Linden Abby Vander , Poehlman William L. , Chen Xianfeng , Baheti Saurabh , Ho Charlotte C.G. , Nguyen Thuy , Yepez‐Sisalema Geovanna , Mitchell Adriana O , Oatman Stephanie R , Wang Xue , Carrasquillo Minerva M. , Runnels Alexi , Beach Thomas G. , Golde Todd , Barnes Lisa L. , Haroutunian Vahram , Zhang Bin , Jager Philip L. De , Bennett David A. , Greenwood Anna , Ertekin‐Taner Nilüfer , Levey Allan I. , Wingo Aliza P. , Wingo Thomas S. , Seyfried Nicholas T ,   Accelerating Medicine Partnership for Alzheimer’s (AMP‐AD) Diversity Initiative Disease
Published: January 2025

Background

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non‐Hispanic White (NHW) population. To address this, Accelerating Medicines Partnership in AD (AMP‐AD) aimed to promote inclusivity in multi‐omics AD research, to unravel unique molecular signatures and pathways. The study aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial groups.

Method

Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (980 unique individuals), 322 were from African American donors, 214 from Latino Americans, 551 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG samples, 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag‐based mass spectrometry (TMT‐MS). Following quality control (QC), proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. Differential protein expression was conducted within and across races after adjusting for batch using regression‐analysis.

Result

In total, 9,180 proteins from the DLPFC, and 9,734 proteins from STG brain tissues were quantified by TMT‐MS. Further analysis identified approximately 3,000 differentially abundant proteins in AD brains compared to controls within race. The AD‐associated differentially abundant proteins were strongly correlated between DLPFC and STG regions and with CERAD and Braak. Protein levels of MAPT and APP demonstrated equivalent disease‐related elevations in both African American and NHW individuals with AD. Notably, after adjusting for AD, significant differences in protein levels were identified across race.

Conclusion

The proteomics approach employed by AMP‐AD sheds light on the brain proteome in AD across diverse racial groups, emphasizing the importance of inclusive research in establishing robust and generalizable discoveries. The identified proteins here could underscore racial disparities beyond disease association, contributing to a more nuanced understanding of AD pathophysiology.