Neurological conditions have emerged as the leading global cause of illness and disability, impacting more than 3 billion people.¹ Among these, neurodegenerative diseases stand out for their relentless progression, lack of curative treatments, and their rising prevalence within aging populations. In particular, Alzheimer’s disease is known for its slow onset and progressive deterioration, and the lack of a cure underscores the critical need to deepen our understanding of the molecular cues that lead to neurodegeneration, with the goal of identifying effective preventative and therapeutic measures.

Neurodegenerative diseases like Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and Huntington’s are all characterised by disrupted proteome homeostasis and selective neuronal loss. These conditions have become a significant burden for an ageing society, with one-third of people in industrialised nations expected to develop a neurodegenerative disease during their lifetime.¹ Their extended disease courses, progressive deterioration, and necessity for long-term care underscore the urgency of understanding the molecular mechanisms driving neurodegeneration.

Mass spectrometry (MS)-based proteomics serves as a powerful window into neurodegeneration, enabling researchers to comprehensively analyse changes in protein abundance, modifications, interactions, and degradation pathways. A key advance of this approach is the study of proteoforms—the structurally and functionally diverse protein variants derived from the same gene as a result of genetic variation, alternative splicing, and post-translational modifications (PTMs). Investigating proteoforms sheds new light on protein function and dysfunction within neurodegenerative disease contexts and is crucial for resolving complex disease mechanisms.