TY - JOUR
T1 - Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease
AU - Visser, Pieter Jelle
AU - Reus, Lianne M
AU - Gobom, Johan
AU - Jansen, Iris
AU - Dicks, Ellen
AU - van der Lee, Sven J
AU - Tsolaki, Magda
AU - Verhey, Frans R J
AU - Popp, Julius
AU - Martinez-Lage, Pablo
AU - Vandenberghe, Rik
AU - Lleó, Alberto
AU - Molinuevo, José Luís
AU - Engelborghs, Sebastiaan
AU - Freund-Levi, Yvonne
AU - Froelich, Lutz
AU - Sleegers, Kristel
AU - Dobricic, Valerija
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Vos, Stephanie J B
AU - Bos, Isabelle
AU - Smit, August B
AU - Blennow, Kaj
AU - Scheltens, Philip
AU - Teunissen, Charlotte E
AU - Bertram, Lars
AU - Zetterberg, Henrik
AU - Tijms, Betty M
AU - Alzheimer's Disease Neuroimaging Initiative
N1 - © 2022. The Author(s).
PY - 2022/3/28
Y1 - 2022/3/28
N2 - 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.
AB - 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.
KW - Alzheimer Disease/cerebrospinal fluid
KW - Biomarkers/cerebrospinal fluid
KW - Humans
KW - Neuronal Plasticity
KW - Proteomics
KW - tau Proteins/cerebrospinal fluid
KW - Biomarker discovery
KW - Neuronal plasticity
KW - TRANSCRIPTION
KW - AMYLOID PRECURSOR PROTEIN
KW - CELL-CYCLE PROGRESSION
KW - BLOOD-BRAIN-BARRIER
KW - ADULT
KW - Cerebrospinal fluid proteomics
KW - BIOMARKERS
KW - Heterogeneity
KW - REST
KW - Molecular mechanisms
KW - ENRICHMENT
KW - GENERATION
KW - WIDE
KW - Alzheimer's disease
U2 - 10.1186/s13024-022-00521-3
DO - 10.1186/s13024-022-00521-3
M3 - Article
C2 - 35346299
SN - 1750-1326
VL - 17
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 27
ER -