Diagnostic and progression biomarkers in cerebrospinal fluid of Alzheimer’s disease patients

(2024) 22:60 Chatanaka et al. BMC Medicine https://doi.org/10.1186/s12916-024-03270-w BMC Medicine CORRESPONDENCE Open Access Diagnostic and progression biomarkers in cerebrospinal fluid of Alzheimer’s disease patients Miyo K. Chatanaka1, Ioannis Prassas2 and Eleftherios P. Diamandis3*    Abstract In this commentary, we address a paper published by Johnson et al. by assessing the robustness of their method to discover diagnostic biomarkers in Alzheimer’s disease (AD). In addition, we examine how these newly discovered and previously discovered biomarkers, can play a role in assisting patients with AD and those at risk for developing AD, with an emphasis on the translational hurdles that accompany such discoveries. Keywords Alzheimer’s disease, Biomarker, Non-invasive, SMOC1, Neuropentraxin, Diagnostic test, Reference range Introduction Recently, Johnson et al. and the Dominantly Inherited Alzheimer Network (DIAN) published an excellent paper describing the discovery of new diagnostic and progression biomarkers for Alzheimer’s disease (AD) in cerebrospinal fluid (CSF) of patients with mutant or wild-type genes, namely amyloid precursor protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2) [1]. They identified SPARC-related modular calcium-binding protein 1 (SMOC1) and another 33 proteins that are significantly altered (increased or decreased during the disease course) in autosomal dominant Alzheimer disease (ADAD) mutation carriers, in comparison to non-carriers. Using these biomarkers, they correctly categorized carriers from noncarriers across the disease time course and compared their data with current and emerging Aβ, phosphorylated *Correspondence: Eleftherios P. Diamandis 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada 2 Laboratory Medicine Program, University Health Network, Toronto, ON, Canada 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada tau (pTau), and other biomarkers. These new, single, or composite biomarkers, whose concentration is changing over many years (sometimes 40 years earlier than clinical AD manifestation) have the potential to be used for both sporadic (common) or inherited (very rare) AD risk stratification, in efforts to prevent, or slow down progression by using current and emerging therapies. The same group has recently published additional data by analyzing 1305 proteins in brain tissue, CSF, and plasma from patients with sporadic AD, triggering receptor expressed on myeloid cells 2 (TREM2) risk variant carriers, patients with ADAD, and healthy individuals and they identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD [2]. In this commentary we wish to address two issues: 1. To assess the robustness of their biomarker discovery strategy described in [1] by comparing their new biomarkers with already reported predictive biomarkers in CSF of late-onset AD (LOAD); 2. To examine how these newly discovered and additional biomarkers could be used to help AD patients or those at risk for developing AD in the future, with emphasis on potential translational hurdles. © The Author(s) 2024. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Chatanaka et al. BMC Medicine (2024) 22:60 The authors of the ADAD paper [1] assembled a group (N = 59) of promising progression AD biomarkers based on prior findings in LOAD patients described in multiple studies, including our own [3–9]. Of these, 33 were informative (Fig. 2) and were measured once in CSF of ADAD patients (carriers and noncarriers) cross-sectionally, by using selected reaction monitoring (SRM) mass spectrometry. By calculating the approximate timing of ADAD clinical manifestations, and using molecular family data, they modeled biomarker changes before and after clinical disease manifestation in both carriers and non-carriers. Some plots of biomarker changes over time, in relation to the approximate calculated timing of disease onset are presented in the paper (their Fig. 1). In our own papers with a similar objective (3–5; not referenced by Johnson et al.), we assembled a list of 30 CSF proteins by selecting brain-specific proteins, using Protein Atlas, that were also present in one, or both, CSF proteomes from apparently normal individuals and LOAD [4]. Our detailed rationale and findings are described in our cited papers [3–5]. We then measured the 30 selected proteins by SRM mass spectrometry in CSFs from cognitively normal, mild cognitive impairment (MCI), moderate, and severe LOAD [5]. Among the proteins that were altered, 5 proteins were common between the study of Johnson et al. and ours. We confirmed these to be proteins whose concentration changes with LOAD progression from normal, to MCI, to moderate, and to severe AD. As expected, these five proteins belonged to the fifth category of proteins (as categorized by Johnson et al.) which coincide with the onset of brain atrophy and are decreased in CSF of LOAD. These included neuronal and neurosecretory proteins such as VGF, neuropentraxin, and its receptor (NPTX and NPTXR, respectively), suggesting considerable synaptic and neuronal loss. The decreases of CSF NPTXR in LOAD were confirmed by multiple methods and were found to correlate with amyloid load and PET findings [7–9]. We concluded that the discovery strategies between the Johnson et al. and our own studies provide partially similar, overlapping data, even if the patient samples used are very different (LOAD vs ADAD) and come from different biobanks. However, due to the relatively small number of the selected proteins for SRM quantification in the two studies (< 100), we are almost certain that additional proteins in CSF, which change concentration as the disease progresses, likely exist, if it is considered that the CSF proteome contains at least 3000 proteins [3, 4]. The newer work of Johnson et al. [2] confirmed this suggestion. Page 2 o (...truncated)