APOE ϵ4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
Konijnenberg, Elles (Alzheimer Center Amsterdam)
Tijms, Betty M. (Alzheimer Center Amsterdam)
Gobom, Johan (University of Gothenburg)
Dobricic, Valerija (University of Lübeck)
Bos, Isabelle (Maastricht University)
Vos, Stephanie (Maastricht University)
Tsolaki, Magda (AHEPA University Hospital (Grècia))
Verhey, Frans (Maastricht University)
Popp, Julius (Lausanne University Hospital)
Martinez-Lage, Pablo (Fundación CITA-Alzhéimer Fundazioa (San Sebastián, País Basc))
Vandenberghe, Rik (University Hospitals Leuven (Bèlgica))
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Frölich, Lutz (University of Heidelberg)
Lovestone, Simon (Janssen RandD)
Streffer, Johannes (Janssen RandD)
Bertram, Lars (University of Oslo)
Blennow, Kaj (University of Gothenburg)
Teunissen, Charlotte E. (Vrije Universiteit Amsterdam)
Veerhuis, Robert (Vrije Universiteit Amsterdam)
Smit, August B. (Vrije Universiteit Amsterdam)
Scheltens, Philip (Vrije Universiteit Amsterdam)
Zetterberg, Henrik (UK Dementia Research Institute)
Visser, Pieter Jelle (Karolinska Instutet)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ϵ4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ϵ4 genotype. We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ϵ4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ϵ4 allele (average age 75 ± 6 years). One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ϵ4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ϵ4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.
Derechos:	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.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Amyloid aggregation ; APOE genotype ; CSF proteomics
Publicado en:	Alzheimer's research & therapy, Vol. 12 Núm. 1 (27 2020) , p. 65, ISSN 1758-9193

DOI: 10.1186/s13195-020-00628-z
PMID: 32460813

11 p, 1.4 MB

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