Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
Visser, Pieter Jelle (Karolinska Institutet (Estocolm, Suècia))
Reus, Lianne M. (Vrije Universiteit Amsterdam)
Gobom, Johan (Sahlgrenska Academy at the University of Gothenburg)
Jansen, Iris E (VU University)
Dicks, Ellen (Vrije Universiteit Amsterdam)
van der Lee, Sven J. (Vrije Universiteit Amsterdam)
Tsolaki, Magda (AHEPA University Hospital (Grècia))
Verhey, Frans R. J. (Maastricht University)
Popp, Julius (University Hospital Zurich (Suïssa))
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa)
Vandenberghe, Rik (KU Leuven)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Molinuevo, José Luis (Hospital Clínic i Provincial de Barcelona)
Engelborghs, Sebastiaan (Vrije Universiteit Brussel)
Freund-Levi, Yvonne (Örebro University)
Froelich, Lutz (University of Heidelberg)
Sleegers, Kristel (University of Antwerp)
Dobricic, Valerija (University of Lübeck)
Lovestone, Simon (High Wycombe, UK)
Streffer, Johannes (AC Immune SA)
Vos, Stephanie J. B. (Maastricht University)
Bos, Isabelle (Maastricht University)
Smit, August B. (Vrije Universiteit Amsterdam)
Blennow, Kaj (Sahlgrenska Academy at the University of Gothenburg)
Scheltens, Philip (Vrije Universiteit Amsterdam)
Teunissen, Charlotte E. (Amsterdam University Medical Centers (AUMC))
Bertram, Lars (University of Oslo)
Zetterberg, Henrik (Dementia Research Institute at UCL)
Tijms, Betty M. (Vrije Universiteit Amsterdam)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles. The online version contains supplementary material available at 10. 1186/s13024-022-00521-3.
Ajuts:	European Commission 681712
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Alzheimer's disease ; Molecular mechanisms ; Biomarker discovery ; Heterogeneity ; Neuronal plasticity ; Cerebrospinal fluid proteomics
Publicat a:	Molecular neurodegeneration, Vol. 17 (march 2022) , ISSN 1750-1326

DOI: 10.1186/s13024-022-00521-3
PMID: 35346299

16 p, 2.1 MB

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