The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

Abstract

Beyond the core features of Alzheimer’s disease (AD) pathology, i.e. amyloid pathology, tau-related neurodegeneration and microglia response, multiple other molecular alterations and pathway dysregulations have been observed in AD. Their inter-individual variations, complex interactions and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical levels complicates diagnosis, prognosis, treatment and drug design and testing. High-throughput “omics” comprise unbiased and untargeted data-driven methods which allow the exploration of a wide spectrum of disease-related changes at different endophenotype levels without focussing a priori on specific molecular pathways or molecules. Crucially, new methodological and statistical advances now allow for the integrative analysis of data resulting from multiple and different omics methods. These multi-omics approaches offer the unique advantage of providing a more comprehensive characterisation of the AD endophenotype and to capture molecular signatures and interactions spanning various biological levels. These new insights can then help decipher disease mechanisms more deeply. In this review, we describe the different multi-omics tools and approaches currently available and how they have been applied in AD research so far. We discuss how multi-omics can be used to explore molecular alterations related to core features of the AD pathologies and how they interact with comorbid pathological alterations. We further discuss whether the identified pathophysiological changes are relevant for the clinical manifestation of AD, in terms of both cognitive impairment and neuropsychiatric symptoms, and for clinical disease progression over time. Finally, we address the opportunities for multi-omics approaches to help discover novel biomarkers for diagnosis and monitoring of relevant pathophysiological processes, along with personalised intervention strategies in AD.

The future is precision medicine-guided diagnoses, preventions and treatments for neurodegenerative diseases

“…Precision medicine will play a key role toward a personalized approach needed to treat complex neurodegenerative diseases. This has been steadily gaining traction for some time, but now with the advent of artificial intelligence, new generation genetics and multi-omics screenings (Baxter et al, 2021;Dong et al, 2021;Clark et al, 2022), paired with state-of-the-art technology, the field is approaching a point that personalized medicine could now become a reality. New departments focused on precision medicine are being formed at academic, governmental, non-profit and forprofit institutions around the globe.…”

Integrative multi-omics and systems bioinformatics in translational neuroscience: A data mining perspective

“…Unsupervised integration of multi-omics datasets has been mainly used in primary research, including AD, PD and ALS studies [ 4 , 12 , 227 , 228 ]. Recently, this approach has been adopted by neurodegenerative disease related data mining studies.…”

“…In addition, data mining overcomes the technical challenges in conducting the initial experiments such as difficulty in obtaining precious tissue samples, stringent requirements in sample preparation, and high cost, while creating opportunities for new diagnostic and therapeutic strategies targeting neurodegenerative diseases. While single omics analyses have provided valuable disease mechanistic insights, recent studies have shown that integrative multi-omics analysis can help to define the connection and relationship among the different types of omics datasets to unravel brain networks regulating transitions from health to the development of neurological diseases and to classify clinically relevant subgroups to identify potential biomarkers [ 11 , 12 ].…”

Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease

“…Cross-omics approaches can reveal not only how complex biomolecular profiles change in association with a disease, but also the relationships and correlations between distinct classes of biological molecules. Their potential for studying neurodegeneration has been previously described [24][25][26][27][28][29][30][31][32][33][34]. However, only recently has the deep molecular characterization of multiple cortical regions from diverse brain banks and cohorts been generated [2,3], enabling a more detailed and comprehensive examination of cross-omics data in AD.…”