Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
Por:
Visser, PJ, Reus, LM, Gobom, J, Jansen, I, Dicks, E, Van der Lee, SJ, Tsolaki, M, Verhey, FRJ, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lleo, A, Molinuevo, JL, Engelborghs, S, Freund-Levi, Y, Froelich, L, Sleegers, K, Dobricic, V, Lovestone, S, Streffer, J, Vos, SJB, Bos, I, Smit, AB, Blennow, K, Scheltens, P, Teunissen, CE, Bertram, L, Zetterberg, H, Tijms, BM
Publicada:
28 mar 2022
Resumen:
Background 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. Methods 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. Results 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. Conclusions 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.
Filiaciones:
Visser, PJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden
Reus, LM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Gobom, J:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Jansen, I:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam Neurosci, Dept Complex Trait Genet, Amsterdam, Netherlands
Dicks, E:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Van der Lee, SJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Genet, Sect Genom Neurodegenerat Dis & Aging, Amsterdam UMC, Amsterdam, Netherlands
Tsolaki, M:
AHEPA Univ Hosp, Dept Neurol 1, Thessaloniki, Makedonia, Greece
Verhey, FRJ:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands
Popp, J:
Univ Hosp Lausanne, Old Age Psychiat, Lausanne, Switzerland
Univ Hosp Psychiat, Dept Geriatr Psychiat, Zurich, Switzerland
Univ Zurich, Zurich, Switzerland
Martinez-Lage, P:
Fdn CITA Alzheimer Fundazioa, San Sebastian, Spain
Vandenberghe, R:
Univ Hosp Leuven, Neurol Serv, Leuven, Belgium
Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium
Lleo, A:
Univ Autonoma Barcelona, IIB St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain
Molinuevo, JL:
Barcelonassta Brain Res Ctr BBRC, Barcelona, Spain
Hosp Clin Barcelona, Alzheimers Dis Unit, Barcelona, Spain
Hosp Clin Barcelona, Other Cognit Disorders Unit, Barcelona, Spain
Engelborghs, S:
Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium
Vrije Univ Brussel, UZ Brussel, Dept Neurol, Brussels, Belgium
Vrije Univ Brussel, Ctr Neurosci, Brussels, Belgium
Freund-Levi, Y:
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden
Orebro Univ, Dept Psychiat Sch Med Sci, Orebro, Sweden
Froelich, L:
Heidelberg Univ, Zentralinst Seel Gesundheit, Dept Geriatr Psychiat, Mannheim, Germany
Sleegers, K:
VIB, VIB Ctr Mol Neurol, Complex Genet Grp, Antwerp, Belgium
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Dobricic, V:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Lovestone, S:
Jansen UK, High Wycombe, Bucks, England
Streffer, J:
Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium
AC Immune SA, Lausanne, Switzerland
Vos, SJB:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands
Bos, I:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands
Smit, AB:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, Amsterdam Neurosci, Amsterdam, Netherlands
Blennow, K:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Scheltens, P:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Teunissen, CE:
Amsterdam Univ Med Ctr AUMC, Dept Clin Chem, Neurochem Lab, Amsterdam Neurosci, Amsterdam, Netherlands
Bertram, L:
Univ Antwerp, Dept Biomed Sci, Antwerp, Belgium
Univ Oslo, Dept Psychol, Ctr Lifespan Changes Brain & Cognit, Oslo, Norway
Zetterberg, H:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
UCL Inst Neurol, Dept Neurodegenerat Dis, London, England
UCL, Dementia Res Inst, London, England
Tijms, BM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci, POB 7057, NL-1007 MB Amsterdam, Netherlands
Green Published, gold, All Open Access, Gold, Green
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