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Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum
Open accessAbstract
Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys ® immunoassays to measure cerebrospinal fluid (CSF) amyloid‐β (Aβ)42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α‐synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum . Results: CSF t‐tau, p‐tau, and neurogranin increase throughout aging only in Aβ‐positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p‐tau and p‐tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p‐tau; t‐tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum .
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“The CSF sample collection and processing followed standard procedures25 and have been described previously15.”
From Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease (2022) · cites this paper as [15]
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Method
Cited by
Sorted by citations
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Self-citationBlood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview
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“The following immunoassays were performed on a cobas e 601 analyzer: Elecsys β-amyloid(1-42) CSF, Elecsys Phospho-Tau (181P) CSF and Elecsys Total-Tau CSF, S100 calcium binding protein B (S100B), and interleukin-6 (IL6).”
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Self-citationSystematic Assessment of 10 Biomarker Candidates Focusing on α‐Synuclein‐Related Disorders
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“If well validated in the context of the pathophysiological progression of AD, synaptic biomarkers can potentially be used to monitor disease progression and treatment effects 30 .”
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Self-citationComparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers
Mielke, M. M., Przybelski, S. A., Lesnick, T. G., Kern, S., Zetterberg, H., Blennow, K., Knopman, D. S., Graff‐Radford, J., Petersen, R. C., Jack, C. R., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12239 · Cited by 30
Self-citationSalvadó, G., Milà‐Alomà, M., Shekari, M., Minguillón, C., Fauria, K., Niñerola‐Baizán, A., Perissinotti, A., Kollmorgen, G., Buckley, C. J., Farrar, G., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12245 · Cited by 30
“CSF Aβ42 was measured using the Elecsys® β- amyloid(1-42),15 while t-tau and p-tau were measured using the electrochemiluminescence immunoassays Elecsys® Total-Tau and Phospho-Tau(181P) CSF on a fully automated cobas e 601 instrument (Roche Diagnostics International Ltd.”
MethodSelf-citationNeuroinflammation Biomarkers in the AT(N) Framework Across the Alzheimer's Disease Continuum
Bieger, A., Rocha, A., Bellaver, B., Machado, L. S., Ros, L. U. D., Borelli, W. V., Therriault, J., Macedo, A. C., Pascoal, T. A., Gauthier, S. G., et al. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.54 · Cited by 29
“However, an association was observed between CSF GFAP and Aβ pathology in CU individuals, as assessed by PET and CSF biomarkers (62, 63).”
BackgroundSex/gender effects of glial reactivity on preclinical Alzheimer’s disease pathology
Vila‐Castelar, C., Akinci, M., Palpatzis, E., Dominguez, P. A., Operto, G., Kollmorgen, G., Quijano‐Rubio, C., Blennow, K., Zetterberg, H., Falcón, C., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02753-9 · Cited by 32
“CSF YKL40 and GFAP were used as markers of astroglial-related response [45].”
Self-citationGrau‐Rivera, O., Navalpotro‐Gómez, I., Sánchez‐Benavides, G., Suárez‐Calvet, M., Milà‐Alomà, M., Arenaza‐Urquijo, E. M., Salvadó, G., Sala‐Vila, A., Shekari, M., Gónzalez‐de‐Echávarri, J. M., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00781-z · Cited by 26
“We used in-house published CSF cutoffs to define biomarker profiles [22].”
BackgroundMethodInfluentialSelf-citationZhai, X., Yan, W., Liu, S., Tian, L., Zhang, Y., Zhao, Y., Ni, Y., Shen, H., Wang, J., Wan, Z., et al. (2024) · Environmental Pollution · doi:10.1016/j.envpol.2024.123555 · Cited by 24
Mravinacová, S., Alanko, V., Bergström, S., Bridel, C., Pijnenburg, Y. A. L., Hagman, G., Kivipelto, M., Teunissen, C. E., Nilsson, P., Matton, A., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00705-z · Cited by 25
“Only weak correlations were observed between these proteins and NfL, which is in accordance with previous studies suggesting that NfL and synaptic markers reflect different neurodegenerative processes [12, 30].”
ResultDaniilidou, M., Holleman, J., Hagman, G., Kåreholt, I., Aspö, M., Brinkmalm, A., Zetterberg, H., Blennow, K., Solomon, A., Kivipelto, M., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03072-x · Cited by 27
Self-citationGenetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum
Vilor‐Tejedor, N., Genius, P., Rodríguez‐Fernández, B., Minguillón, C., Sadeghi, I., González‐Escalante, A., Crous‐Bou, M., Suárez‐Calvet, M., Grau‐Rivera, O., Brugulat‐Serrat, A., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13537 · Cited by 21
Self-citationJacobs, T., Jacobson, S. R., Fortea, J., Berger, J. S., Vedvyas, A., Marsh, K., He, T., Gutiérrez‐Jiménez, E., Fillmore, N. R., Gonzalez, M., et al. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00435-2 · Cited by 27
Self-citationZhang, Y., Guo, Y. X., He, Y., You, J., Zhang, Y., Wang, L., Chen, S., He, X., Yang, L., Huang, Y., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02840-x · Cited by 26
González‐Escalante, A., Milà‐Alomà, M., Brum, W. S., Ashton, N. J., Ortiz-Romero, P. L., Shekari, M., del Campo, M., Anastasi, F., Quijano‐Rubio, C., Kollmorgen, G., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105741 · Cited by 26
“23 [18F] fl utemetamol PET acquisition and quanti fi cation was previously described.”
Self-citationSánchez‐Benavides, G., Suárez‐Calvet, M., Milà‐Alomà, M., Arenaza‐Urquijo, E. M., Grau‐Rivera, O., Operto, G., Gispert, J. D., Vilor‐Tejedor, N., Sala‐Vila, A., Crous‐Bou, M., et al. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.02.026 · Cited by 22
Self-citationSchmidt-Morgenroth, I., Michaud, P., Gasparini, F., & Avraméas, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310523 · Cited by 26
Esquer, A., Blanc, F., & Collongues, N. (2023) · Neurology and Therapy · doi:10.1007/s40120-023-00541-1 · Cited by 25
“Amyloid lesions often appear to precede the tau lesions [11].”
BackgroundCumplido‐Mayoral, I., Brugulat‐Serrat, A., Sánchez‐Benavides, G., González‐Escalante, A., Anastasi, F., Milà‐Alomà, M., López‐Martos, D., Akinci, M., Falcón, C., Shekari, M., et al. (2024) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(24)00025-4 · Cited by 23
Self-citationPelkmans, W., Vromen, E. M., Dicks, E., Scheltens, P., Teunissen, C. E., Barkhof, F., van der Flier, W. M., Tijms, B. M., & Initiative, A. D. N. (2022) · Brain Communications · doi:10.1093/braincomms/fcac026 · Cited by 21
Johnson, S. C., Suárez‐Calvet, M., Suridjan, I., Minguillón, C., Gispert, J. D., Jonaitis, E. M., Michna, A., Carboni, M., Bittner, T., Rabe, C., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01168-y · Cited by 25
Self-citationPeripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer’s Disease
Weber, G. E., Khrestian, M., Tuason, E. D., Shao, Y. Y., Pillai, J. A., Rao, S. M., Feng, H., Zhou, Y., Cheng, F., DeSilva, T. M., et al. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2100771 · Cited by 22
CSF glial biomarkers are associated with cognition in individuals at risk of Alzheimer's disease
Warmenhoven, N., Sánchez‐Benavides, G., González‐Escalante, A., Milà‐Alomà, M., Shekari, M., López‐Martos, D., Ortiz‐Romero, P., Kollmorgen, G., Quijano‐Rubio, C., Minguillón, C., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13862 · Cited by 22
Self-citationBonomi, C. G., Assogna, M., Donna, M. G. D., Bernocchi, F., Lucia, V. D., Nuccetelli, M., Fiorelli, D., Loizzo, S., Mercuri, N. B., Koch, G., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-221010 · Cited by 20
Milà‐Alomà, M., Shekari, M., Salvadó, G., Gispert, J. D., Arenaza‐Urquijo, E. M., Operto, G., Falcón, C., Vilor‐Tejedor, N., Grau‐Rivera, O., Sala‐Vila, A., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00863-y · Cited by 20
“The cutoff was defined as the mean minus 2 standard deviations (SD) of the non-pathologic Gaussian distribution of the CSF Aβ42/40 ratio [22].”
MethodSelf-citationDong, R., Denier‐Fields, D. N., Lu, Q., Suridjan, I., Kollmorgen, G., Wild, N., Betthauser, T. J., Carlsson, C. M., Asthana, S., Johnson, S. C., et al. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.04.009 · Cited by 18
Self-citationP-tau subgroups in AD relate to distinct amyloid production and synaptic integrity profiles
Wesenhagen, K. E. J., Tijms, B. M., Boonkamp, L., Hoede, P. L., Goossens, J., Dewit, N., Scheltens, P., Vanmechelen, E., Visser, P. J., & Teunissen, C. E. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01038-z · Cited by 18
“Potentially, associations of p-tau subgroups with amyloid and synaptic markers may be stronger compared to NfL, because structural axonal loss occurs downstream of changes in amyloid production and synaptic damage [22, 41, 42].”
BackgroundDifferential effects of sleep on brain structure and metabolism at the preclinical stages of AD
Stankeviciute, L. S., Falcón, C., Operto, G., García-Prat, M., Shekari, M., Iranzo, Á., Niñerola‐Baizán, A., Perissinotti, A., Minguillón, C., Fauria, K., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13102 · Cited by 18
Self-citationProteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aβ
Matafora, V., Gorb, A., Yang, F., Noble, W. J., Bachi, A., Perez‐Nievas, B. G., & Jiménez-Sánchez, M. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15875 · Cited by 19
Vicente, M. C., Paneghini, J. D. L., Stabile, A. M., Amorim, M. R., Silva, C. E. A., Patrone, L. G. A., Cunha, T. M., Bícego, K. C., Almeida, M. C., Carrettiero, D. C., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230151 · Cited by 21
Sexton, C. E., Solis, M., Aharon‐Peretz, J., Alexopoulos, P., Apostolova, L. G., Bayen, É., Birkenhager, B., Cappa, S. F., Constantinidou, F., Fortea, J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12588 · Cited by 20
Self-citationYan, H., Yan, Y., Gao, Y., Zhang, N., Kumar, G., Fang, Q., Li, Z., Li, J., Zhang, Y., Song, L., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-10554-9 · Cited by 17
Cacciaglia, R., Operto, G., Falcón, C., Gónzalez‐de‐Echávarri, J. M., Sánchez‐Benavides, G., Brugulat‐Serrat, A., Milà‐Alomà, M., Blennow, K., Zetterberg, H., Molinuevo, J. L., et al. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac239 · Cited by 19
“071 were considered as Aβ negative (Milà-Alomà et al. 2020).”
BackgroundMethodSelf-citationSun, J., Duan, S., Xu, W., He, W., Li, T., Liu, S., Hoettges, K. F., Zhu, J., Leach, M. P., & Song, P. (2025) · Analytica Chimica Acta · doi:10.1016/j.aca.2025.344013 · Cited by 16
Wang, X., Zhang, X., Liu, J., Zhang, J., Liu, C., Cui, Y., Song, Q., Hou, Y., Wang, Y., Zhang, Q., et al. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01440-9 · Cited by 15
“CSF samples were immediately collected according to international guidelines [25].”
MethodYu, X., Shi, R., Zhou, X., Zhang, M., Cai, Y., Jiang, J., & Han, Y. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14084 · Cited by 16
Varma, V., An, Y., Kac, P. R., Bilgel, M., Moghekar, A., Loeffler, T., Amschl, D., Troncoso, J. C., Blennow, K., Zetterberg, H., et al. (2024) · medRxiv · doi:10.1101/2024.01.25.24301779 · Cited by 16
Self-citationTau Protein Alterations Induced by Hypobaric Hypoxia Exposure
Pena, E., Martin-Salamanca, R. S., Alam, S. E., Flores, K., & Arriaza, K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25020889 · Cited by 16
López‐Martos, D., Suárez‐Calvet, M., Milà‐Alomà, M., Gispert, J. D., Minguillón, C., Quijano‐Rubio, C., Kollmorgen, G., Zetterberg, H., Blennow, K., Grau‐Rivera, O., et al. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1394460 · Cited by 14
Self-citationPak, V. M., Paul, S., Swieboda, D., Balthazar, M. S., & Wharton, W. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12332 · Cited by 13
Zarei, O., moghaddam, M. T., & Vastegani, S. M. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111667 · Cited by 21
Rosenich, E., Bransby, L., Yassi, N., Fripp, J., Laws, S. M., Martins, R. N., Fowler, C. J., Rainey‐Smith, S. R., Rowe, C. C., Masters, C. L., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000200118 · Cited by 13
“In preclinical AD, Aβ levels are already sufficiently high to result in neurodegeneration and cognitive decline.(46) As such, it is likely that modifiable risk factors have little influence on hippocampal volume loss and memory decline because any potential protective effect once incurred is diminished.”
BackgroundWen, Q., Wittens, M. M. J., Engelborghs, S., van Herwijnen, M. H. M., Tsamou, M., Roggen, E., Smeets, H. J. M., Krauskopf, J., & Briedé, J. J. (2024) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00740 · Cited by 14
P-tau and neurodegeneration mediate the effect of β-amyloid on cognition in non-demented elders
Ma, L., Hu, H., Wang, Z.-T., Ou, Y., Dong, Q., Tan, L., & Yu, J. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00943-z · Cited by 16
“The CSF YKL-40 levels (unit: ng/mL) were measured by the MicroVue YKL-40 ELISA (Quidel Corp.) at the University of Washington [18].”
MethodInfluentialAxonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy
Svenningsson, A. L., Stomrud, E., Palmqvist, S., Hansson, O., & Ossenkoppele, R. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01081-w · Cited by 14
Metadata
- Authors
- Milà‐Alomà, M., Salvadó, G., Gispert, J. D., Vilor‐Tejedor, N., Grau‐Rivera, O., Sala‐Vila, A., Sánchez‐Benavides, G., Arenaza‐Urquijo, E. M., Crous‐Bou, M., González‐de‐Echávarri, J. M., Minguillon, C., Fauria, K., Simon, M., Kollmorgen, G., Zetterberg, H., Blennow, K., Suárez‐Calvet, M., Molinuevo, J. L., & study, F. T. A.
- Affiliations
- Universitat Pompeu Fabra (ES)
- Pasqual Maragall Foundation (ES)
- Barcelonaβeta Brain Research Center (BBRC) Pasqual Maragall Foundation Barcelona Spain
- Harvard University (US)
- F. Hoffmann-La Roche AG (CH)
- Roche Diagnostics GmbH Penzberg Germany
- Sahlgrenska University Hospital (SE)
- Corresponding author
- Suárez‐Calvet, Marc
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-06-23
- Volume
- 16
- Issue
- 10
- Pages
- 1358-1371
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC7586814
- OpenAlex
- W3037038790
- Cited by
- 241
- References
- 51
- Citations by year
- 2026: 30 · 2025: 45 · 2024: 53 · 2023: 34 · 2022: 41 · 2021: 33 · 2020: 5
- FWCI
- 17.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by-nc-nd)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- “la Caixa” Foundation (ID 100010434)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- preclinical Alzheimer's disease
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Nerve Degeneration, Neuroglia, Synapses, Biomarkers, Amyloid beta-Peptides, tau Proteins, Prodromal Symptoms
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