Novel, specific protein structural biomarkers for Alzheimer's disease and dementia with Lewy bodies

Neurodegenerative diseases are increasingly prevalent in aging human societies, causing significant suffering and a growing socio-economic burden. Despite having distinct underlying molecular mechanisms, these diseases still overlap in signs, symptoms and pathological features. This hinders accurate diagnosis, negatively affecting disease management, patient enrolment in clinical trials, and development of specific therapies. Robust and disease-specific biomarkers are essential tools for improving the diagnosis and gaining better insights into the molecular pathways involved in these pathologies.

While biomarkers for Alzheimer's disease (AD) (e.g., Aβ42/Aβ40 ratio, total and phosphorylated Tau levels) are currently used in diagnostics, reliable biomarkers for Parkinson"s disease (PD) are still missing. For example, the use of the oligomeric:total alpha-synuclein ratio, a PD hallmark, is impeded by inconsistencies across studies and lack of specificity. The situation is even worse for Dementia with Lewy Bodies (DLB), an under-diagnosed disorder that shares features with AD and PD, and for which no biomarkers are available.

In a previous work (1), we have shown that the global analysis of protein structures in cerebrospinal fluid (CSF) of PD patients constitutes a novel, orthogonal readout for the disease state. Protein structural information could indeed better discriminate between PD patients and healthy individuals than protein abundance information, the typical readout for protein-based biomarker screens. Furthermore, the newly identified protein structural biomarkers were linked to disease mechanisms and provided complementary information to the gold standard alpha-synuclein.

In this study, we extended this approach to the study of AD and DLB, aiming to assess the specificity of our previously identified CSF biomarkers for PD and to discover novel structural biomarker specific to AD and DLB. We used Limited Proteolysis coupled to Mass Spectrometry (LiP-MS) to generate structural fingerprints of proteins in the CSF of 50 individuals with AD, 50 with DLB and 50 with subjective cognitive decline (SCD) as a reference. After correcting for covariates, we are now performing a pair-wise comparison to identify structurally altered proteins in the CSF of AD and DLB patients. I will present the results of these analyses, the identified candidate biomarkers and discuss the emerging concept of structural disease biomarkers and its impact in the study of pathological processes.

Mackmull, Marie-Therese et al. "Global, in situ analysis of the structural proteome in individuals with Parkinson's disease to identify a new class of biomarker." Nature structural & molecular biologyvol. 29,10 (2022): 978-989. doi:10.1038/s41594-022-00837-0