Novel Fluid Biomarkers to Biologically define Alzheimer's Disease and Frontotemporal Dementia
Authors:   , Hok-A-Hin Yanaika Sylvana 
Published: December 2024

Biofluid biomarkers are crucial for diagnosing neurodegenerative diseases like Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). While cerebrospinal fluid (CSF) markers targeting key AD pathologies (amyloid and tau) aid diagnosis, the complexity of the disease extends beyond these markers. Biomarkers reflecting additional biological processes could better capture its multifactorial nature. Similarly, fluid biomarkers for FTD and other dementias remain limited, highlighting the need for further discovery. The aim of this thesis was to identify and develop novel and specific CSF biomarkers to biologically characterize AD and FTD dementias.

In the first part of this thesis, we described an update of guidelines for pre-analytical handling and biobanking for CSF samples using the aptamer-based arrays and proximity extension assay (PEA) based approach.

The second part of this thesis presents the validation of novel CSF biomarkers for AD that reflect a range of different biological pathways. Chapter 3 shows the potential of THOP1, an amyloid-beta neuropeptidase, as a CSF biomarker for early AD. Chapter 3 also highlighted that the approach we employed, utilizing antibodies in both discovery and validation studies, may facilitate the translation of proteomics findings and accelerate the development of fluid biomarkers. We therefore applied a similar workflow in Chapters 4-5. Chapter 4 presents novel (MIF and sTREM1) and known (sTREM2) CSF proteins related to inflammation processes. These inflammatory-related proteins showed distinct expression profiles along the symptomatic AD continuum. In Chapter 5, we built a panel consisting of five CSF proteins (THOP1, MMP7, DDC, ENO2, ITGB2). Protein concentrations were increased or tended to be increased consistent with our discovery findings with potential for differential diagnosis.

The final part of this thesis studied the identification, neuropathological characterization, and clinical validation of CSF biomarker candidates for FTD and the main neuropathological subtypes (i.e., FTLD-Tau and FTLD-TDP). Chapter 6 shows that YKL-40 was mainly detected in glial cells in FTLD or AD brains. However, no differences in YKL-40 immunoreactivity and tissue protein levels between FTLD or AD compared with controls were observed. This suggests that YKL-40 concentrations in CSF might not reflect changes occurring within these brain regions. Chapter 7 characterized the location and protein levels of APOL1, an FTLD-Tau biomarker candidate. APOL1 was upregulated in FTLD pathology irrespective of the subtypes, indicating a role of this protein in FTD pathophysiology, although these changes were not mirrored in CSF. In Chapter 8, we performed an extensive proteome profiling in CSF from patients with FTD. 43 proteins were specifically dysregulated, enriched in axonal development among others. Two CSF protein panels that discriminated FTD from controls or AD with high accuracy were identified and validated. These panels cover a wide range of ongoing biological processes that could be useful for different contexts of use.

Overall, the studies presented in this thesis demonstrate that by measuring CSF proteins, we can detect a broad spectrum of diverse biological processes in AD and FTD dementias. This research enhances our understanding of the biology underlying these complex neurodegenerative disorders and has the potential to improve clinical diagnosis.