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Background and Objectives.Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer’s disease (AD) pathology. Cerebrospinal fluid (CSF) biomarkers allow the detectionin vivoof AD-related pathological hallmarks included in the AT(N) classification system. Here, we aimed to investigate whether CSF biomarkers of synaptic and neuro-axonal damage are correlated with the presence of AD co-pathology in LBD and can be useful to differentiate LBD patients with different AT(N) profiles.Methods.We retrospectively measured CSF levels of AD core biomarkers (Aβ42/40 ratio, p-tau, t-tau) and of synaptic (β-synuclein, α-synuclein, SNAP-25, neurogranin) and neuro-axonal proteins (NfL) in 28 cognitively unimpaired participants with non-degenerative neurological conditions and 161 participants with a diagnosis of either LBD or AD (at both mild cognitive impairment, AD-MCI, and dementia stages, AD-dem). We compared CSF biomarker levels in clinical and AT(N)-based subgroups.Results.CSF β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL levels did not differ between LBD (n = 101, age = 67.2 ± 7.8 years, 27.7% females) and controls (age = 64.8 ± 8.6 years, 39.3% females) and were increased in AD (AD-MCI n = 30, AD-dem n = 30, age = 72.3 ± 6.0 years, 63.3% females) compared to both groups (p < 0.001 for all comparisons). In LBD, we found increased levels of synaptic and neuro-axonal degeneration biomarkers in patients with A+T+ (LBD/A+T+) than with A-T- profiles (LBD/A-T-) (p < 0.01 for all), and β-synuclein showed the highest discriminative accuracy between the two groups (AUC = 0.938, 95%CI = 0.884 - 0.991). CSF β-synuclein (p = 0.0021), α-synuclein (p = 0.0099) and SNAP-25 concentrations (p = 0.013) were also higher in LBD/A+T+ than in LBD/A+T- cases, which had synaptic biomarkers levels within the normal range. CSF α-synuclein was significantly decreased only in LBD patients with T- profiles compared to controls (p = 0.0448). Moreover, LBD/A+T+ and AD cases did not differ in any biomarker level.Discussion.LBD/A+T+ and AD cases showed significantly increased CSF levels of synaptic and neuro-axonal biomarkers compared to LBD/A-T- and control subjects. LBD patients with AD co-pathology might, thus, experience similar degrees of synaptic dysfunction than pure AD cases.Classification of evidence.This study provides Class II evidence that CSF levels of β-synuclein, α-synuclein, SNAP-25, neurogranin and NfL are higher in patients with AD than in patients with LBD.

Pathophysiological substrate(s) and progression of Parkinson’s disease (PD) with mild cognitive impairment (PD-MCI) are still matter of debate. Baseline cerebrospinal fluid (CSF) neurochemical profile and cognitive changes after 2 years were investigated in a retrospective series of PD-MCI (n = 48), cognitively normal PD (PD-CN, n = 40), prodromal Alzheimer’s disease (MCI-AD, n = 25) and cognitively healthy individuals with other neurological diseases (OND, n = 44). CSF biomarkers reflecting amyloidosis (Aβ42/40 ratio, sAPPα, sAPPβ), tauopathy (p-tau), neurodegeneration (t-tau, NfL, p-NfH), synaptic damage (α-syn, neurogranin) and glial activation (sTREM2, YKL-40) were measured. The great majority (88%) of PD-MCI patients was A-/T-/N-. Among all biomarkers considered, only NfL/p-NfH ratio was significantly higher in PD-MCI vs. PD-CN (p = 0.02). After 2 years, one-third of PD-MCI patients worsened; such worsening was associated with higher baseline levels of NfL, p-tau, and sTREM2. PD-MCI is a heterogeneous entity requiring further investigations on larger, longitudinal cohorts with neuropathological verification.

Background Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson’s disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. Methods In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. Results We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. Conclusions Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

Introductionβ-synuclein (β-syn) is a presynaptic protein, whose cerebrospinal fluid (CSF) levels are increased in patients with Alzheimer’s diseases (AD) showing mild cognitive impairment (MCI) and dementia (dem). Here, we aimed to investigate CSF β-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, α-synuclein (α-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau).MethodsWe measured β-syn, α-syn, t-tau and NfL in CSF of 75 patients with AD (pre-AD n=17, MCI-AD n=28, dem-AD n=30) and 35 controls (subjective memory complaints, SMC-Ctrl n=13, non-degenerative neurological disorders, Dis-Ctrl n=22).ResultsCSF β-syn, α-syn, t-tau were significantly elevated in pre-AD patients compared with controls (pDiscussionCSF β-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.

The synuclein family includes three neuronal proteins, named α-synuclein, β-synuclein, and γ-synuclein, that have peculiar structural features. α-synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies, namely, dementia with Lewy bodies and multisystem atrophy. The role of β-synuclein and γ-synuclein is less well understood in terms of physiological functions and potential contribution to human diseases. α-synuclein has been investigated extensively in both cerebrospinal fluid (CSF) and blood as a potential biomarker for synucleinopathies. Recently, great attention has been also paid to β-synuclein, whose CSF and blood levels seem to reflect synaptic damage and neurodegeneration independent of the presence of synucleinopathy. In this review, we aim to provide an overview on the pathophysiological roles of the synucleins. Because γ-synuclein has been poorly investigated in the field of synucleinopathy and its pathophysiological roles are far from being clear, we focus on the interactions between α-synuclein and β-synuclein in PD. We also discuss the role of α-synuclein and β-synuclein as potential biomarkers to improve the diagnostic characterization of synucleinopathies, thus highlighting their potential application in clinical trials for disease-modifying therapies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau), and total-tau (t-tau) represent core biomarkers of Alzheimer disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work. Methods Fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after 1-month deep freezing (− 80 °C). As an automated platform, we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results In fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%), and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42. These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau. Nevertheless, the Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions Small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cutoffs for fresh and frozen samples are required, larger, multi-center investigations are needed.

The accumulation and misfolding of α-synuclein (α-syn) represent the main pathological hallmark of PD. Overexpression of α-syn and failure of cellular protein degradation systems play a major role in α-syn aggregation. The discovery of PD-associated genes related to the autophagic-lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α-syn accumulates, suggesting that a crosstalk between α-syn aggregation and autophagic-lysosomal impairment may exist. The understanding of autophagic-lysosomal pathway dysfunctions' role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic-lysosomal pathway impairment and misfolded α-syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic-lysosomal pathway restoration as a disease-modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society.

Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells. The aggregated aSyn species (oligomers and fibrils) exhibited more pronounced accumulation within recipient cells than aSyn monomers. In particular, internalized extracellular aSyn in the aggregated forms was able to seed the aggregation of endogenous aSyn. Following uptake, aSyn was detected along endosome-to-lysosome and autophagosome-to-lysosome routes. Intriguingly, aggregated aSyn resulted in lysosomal activity impairment, accompanied by the accumulation of dilated lysosomes. Moreover, analysis of autophagy-related protein markers suggested decreased autophagosome clearance. In contrast, the endocytic pathway, proteasome activity, and mitochondrial homeostasis were not substantially affected in recipient cells. Our data suggests that extracellularly added aggregated aSyn primarily impairs lysosomal activity, consequently leading to aSyn accumulation within recipient cells. Importantly, the autophagy inducer trehalose prevented lysosomal alterations and attenuated aSyn accumulation within aSyn-exposed cells. Our study underscores the importance of lysosomes for the propagation of aSyn pathology, thereby proposing these organelles as interventional targets.

The accumulation and deposition of α-synuclein aggregates in brain tissue is the main event in the pathogenesis of different neurodegenerative disorders grouped under the term of synucleinopathies. They include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. To date, the diagnosis of any of these disorders mainly relies on the recognition of clinical symptoms, when the neurodegeneration is already in an advanced phase. In the last years, several efforts have been carried out to develop new diagnostic tools for early diagnosis of synucleinopathies, with special interest to Parkinson's disease. The Protein-Misfolding Cyclic Amplification (PMCA) and the Real-Time Quaking-Induced Conversion (RT-QuIC) are ultrasensitive protein amplification assays for the detection of misfolded protein aggregates. Starting from the successful application in the diagnosis of human prion diseases, these techniques were recently tested for the detection of misfolded α-synuclein in brain homogenates and cerebrospinal fluid samples of patients affected by synucleinopathies. So far, only a few studies on a limited number of samples have been performed to test PMCA and RT-QuIC diagnostic reliability. Neverthless, these assays have shown very high sensitivity and specificity in detecting synucleinopathies even at the pre-clinical stage. Despite the application of PMCA and RT-QuIC for α-synuclein detection in biological fluids is very recent, these techniques seem to have the potential for identifying subjects that will be likely to develop synucleinopathies.

Introduction: the current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests. Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients. Results: the (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis. Discussion: this is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD. This manuscript was facilitated by the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), through the Biofluid Based Biomarkers Professional Interest Area (BBB-PIA). The views and opinions expressed in this publication represent those of the authors and do not necessarily reflect those of the BBB-PIA membership, ISTAART, or the Alzheimer's Association. The authors thank the French Society of Clinical Biology, the ISTAART BBB-PIA, and the Society for Neurochemistry and Clinical CSF analysis for their help in initiating this work. Constance Delaby received no support for the present manuscript. Charlotte Teunissen received the following grants during the last 36 months: Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 [MIRIADE], and JPND), Health Holland, the Dutch Research Council (ZonMw), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT and WF are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMw (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. IV is appointed on a research grant by Alzheimer Nederland (NL-17004). She received no support for the present manuscript. Kaj Blennow is supported by the Swedish Alzheimer Foundation (#AF-742881) and Hjärnfonden, Sweden (#FO2017-0243). He received no support for the present manuscript. Daniel Alcolea received funding from Institute of Health Carlos III (ISCIII), Spain PI18/00435 and INT19/00016, and by the Department of Health Generalitat de Catalunya PERIS program SLT006/17/125. He received no support for the present manuscript. Ivan Arisi was partly supported by: Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council and EBRI (2019-2021); POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020” MODIAG Project. Elodie Bouaziz-Amar received no support for the present manuscript. Anne Beaume received no support for the present manuscript. Aurélie Bedel received no support for the present manuscript. Giovanni Bellomo is supported by University of Perugia, CIRMMP, IRST Istituto Romagnolo per lo Studio e la Cura dei Tumori, Innuvatech srl. He received no support for the present manuscript. Edith Bigot-Corbel received no support for the present manuscript. Maria Bjerke received no support for the present manuscript. Marie-Céline Blanc-Quintin received no support for the present manuscript. Mercè Boada received support from LA CAIXA, IMI, ISCIII H2020 the European Union/EFPIA Innovative Medicines Initiative Joint Undertaking MOPEAD project (Grants No. 115985) and is also supported by national grant, PI17/01474 from Acción Estratégica en Salud, integrated into the Spanish National Plan of R+D+I and founded by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). She received no support for the present manuscript. Olivier Bousigues is supported by A2MCL Alsace Alzheimer. He received no support for the present manuscript. Miles D. Chapman received no support for the present manuscript. Mari L. DeMarco is supported by the Michael Smith Foundation for Health Research, Brain Canada (Canada Brain Research Fund), Health Canada, Women's Brain Health Initiative, Alzheimer Society of Canada, St. Paul's Foundation, Djavad Mowafaghian Centre for Brain Health at the University of British Columbia and the Canadian Consortium for Neurodegeneration and Aging; with all funds provided to the University of British Columbia. Mara D'Onofrio was partly supported by Fondo Ordinario Enti (FOE D.M 865/2019) funds in the framework of a collaboration agreement between the Italian National Research Council POR (Operative Program Lazio Region, Italy) FESR (European Program Regional Development) 2014-2020, Public Notice “LIFE 2020″, MODIAG Project. She received no support for the present manuscript. Julien Dumurgier received no support for the present manuscript. Diane Dufour received no support for the present manuscript. Sebastiaan Engelborghs is supported for various projects: Research Project GSKE/FMRE, Research Project FWO Vlaanderen, PhD fellowship FWO Vlaanderen (n = 3), VLAIO PhD fellowship. He received no support for the present manuscript. Hermann Esselmann received no support for the present manuscript. Anne Fogli received no support for the present manuscript. Audrey Gabelle received no support for the present manuscript. Elisabetta Galloni received no support for the present manuscript. Clémentine Gondolf received no support for the present manuscript. Frédérique Grandhomme received no support for the present manuscript. Oriol Grau-Rivera receives grants from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33437), and from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568). He received no support for the present manuscript. Melanie Hart receives UCLH Biomedical Research Centre support from NIHR (Neurosciences). She received no support for the present manuscript. Takeshi Ikeuchi received the following grants to his institution AMED: 21dk0207049, 21dk0207045, 21ek0109545, 20ek0109350, 20ek0109392. He received no support for the present manuscript. Andreas Jeromin received no support for the present manuscript. Kensaku Kasuga received no support for the present manuscript. Ashvini Keshavan is supported by the Weston Brain Institute/Selfridges Foundation grant UB170045. She received no support for the present manuscript. Michael Khalil received unrestricted research grants from Biogen and Novartis. He received no support for the present manuscript. Peter Körtvelyessy received no support for the present manuscript. Agnieszka Kulczynska-Przybik received no support for the present manuscript. Jean-Louis Laplanche received no support for the present manuscript. Qiao-Xin Li received no support for the present manuscript. Alberto Lleó is supported by grants from Generalitat de Catalunya (PERIS SLT002/16/00408), Instituto de Salud Carlos III (PI17/01896), Instituto de Salud Carlos III CIBERNED. He received no support for the present manuscript. Catherine Malaplate received no support for the present manuscript. Marta Marquié is supported by the Instituto de Salud Carlos III (ISCIII) Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa) grant PI19/00335. She received no support for the present manuscript. Colin M. Masters received no support for the present manuscript. Barbara Mroczko received a grant from The Binding Site Group and Biokom Diagnostyka. She received no support for the present manuscript. Léonor Nogueira received no support for the present manuscript. Adelina Orellana received no support for the present manuscript. Markus Otto is supported by BMBF, Thierry Latran foundation, EU, DFG. He received no support for the present manuscript. Jean-Baptiste Oudart is supported by Astrazeneca grant for a research program on EGFR targeted therapy resistance in NSCLC. He received no support for the present manuscript. Claire Paquet received no support for the present manuscript. Federico Paolini received no support for the present manuscript. Lucilla Parnetti received no support for the present manuscript. Armand Perret-Liaudet received no support for the present manuscript. Katell Peoc'h is supported by contract with Siemens Healthineers. She received no support for the present manuscript. Koen Poesen received no support for the present manuscript. Albert Puig-Pijoan received no support for the present manuscript. Isabelle Quadrio received no support for the present manuscript. Murielle Quillard-Muraine received no support for the present manuscript. Benoît Rucheton received no support for the present manuscript. Susanne Schraen received no support for the present manuscript. Jonathan M. Schott is supported by the Medical Research Council, Alzheimer's Research UK, Weston Brain Institute, British Heart Foundation, Alzheimer's Association. He received no support for the present manuscript. Leslie M. Shaw is supported by NIA for ADNI Biomarker Core, UPENN ADRC Biomarker Corr, MJ Fox PPMI for CSF Biomarker measurements, Roche for IIS study of AD biomarkers. He received no support for the present manuscript. Marc Suárez-Calvet receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant agreement No. 948677). He also receives funding from the Instituto de Salud Carlos III (PI19/00155) and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I). He received no support for the present manuscript. Magda Tsolaki received no support for the present manuscript. Hayrettin Tumani is supported by Alexion, Bayer, Biogen, Celgene, Genzyme-Sanofi, Merck, Novartis, Roche, Teva. He received no support for the present manuscript. Chinedu T Udeh-Momoh is supported by Alzheimer research UK (Project Grant). He received no support for the present manuscript. Lucie Vaudran received no support for the present manuscript. Marcel M. Verbeek is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMw within the framework of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch), and the CAFÉ project (the National Institutes of Health, USA, grant number 5R01NS104147-02). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and University of Rhode Island University. MM Verbeek is also supported by a grant from the Selfridges Group Foundation. He received no support for the present manuscript. Federico Verde received no support for the present manuscript. Lisa Vermunt is supported by Alzheimer Nederland. She received no support for the present manuscript. Jonathan Volgesgang is supported by Clinician Scientist Research Fellowship, German Research Foundation (Deutsche Forschungsgesellschaft, project number: 413501650; 09/01/2019-02/28/2021); Eric Dorris Memorial Fellowship (McLean Hospital; 07/01/2020-06/30/2021). He received no support for the present manuscript. Jens Wiltfang is supported by Federal Ministry of Education and Research (BMBF) State of Lower Saxony; He received no support for the present manuscript. Henrik Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. He received no support for the present manuscript. Sylvain Lehmann received no support for the present manuscript.