Alzheimer"s disease (AD), affecting over 24 million people worldwide, remains the leading cause of dementia, underscoring the critical need for new therapeutic targets. Conventional research has predominantly focused on the amyloid cascade hypothesis, which attributes AD pathogenesis to the aggregation of amyloid-β protein1. Yet, this framework inadequately captures the disease's multifaceted symptomology. The presence of neurofibrillary tangles, arising from the hyperphosphorylation and aggregation of tau protein, signals the need for a more expansive research approach.

This study advances our understanding by integrating high-throughput mass spectrometry-based proteomics, metabolomics and lipidomics, offering a comprehensive examination of AD's lipidome, proteome, and metabolome. Analyzing two distinct genotype groups alongside their controls, utilizing mouse plasma samples, the study employed a dual-phase extraction method for metabolomics and lipidomics, the PreOmics ENRICH-iST sample preparation kit for proteomics, and the pioneering Zeno SWATH MS. This data-independent acquisition (DIA) technique, augmented by Zeno trap pulsing, enhances sensitivity, with proteomic data processed via DiaNN software and metabolomics and lipidomic data via oloMAP 2.02.

Our results highlight the Zeno SWATH MS's ability to significantly improve protein identification at both micro and analytical flow-rate chromatographies, even with minimal sample volumes. The analysis delineates clear multiomics distinctions between the groups, notably between genotypes and their controls. Furthermore, the synergy of DDA with SWATH-DIA methodology markedly increases double annotation coverage in lipidomics. The identification of differentially expressed proteins, metabolites and lipids provides new insights into AD's molecular mechanisms, moving beyond the amyloid-centric paradigm. These findings emphasize the potential of uncovering novel AD therapeutic targets in preclinical drug development settings.

References

Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794–799 (2015).Tsugawa, H. et al. A lipidome atlas in MS-DIAL 4. Nat. Biotechnol. 38, 1159–1163 (2020).