APOE epsilon 4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
Por:
Konijnenberg, E, Tijms, BM, Gobom, J, Dobricic, V, Bos, I, Vos, S, Tsolaki, M, Verhey, F, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lleo, A, Frolich, L, Lovestone, S, Streffer, J, Bertram, L, Blennow, K, Teunissen, CE, Veerhuis, R, Smit, AB, Scheltens, P, Zetterberg, H, Visser, PJ
Publicada:
27 may 2020
Resumen:
Background Aggregation of amyloid beta 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) epsilon 4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid beta aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE epsilon 4 genotype. Methods We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE epsilon 4 carriers, average age 75 +/- 7 years) against 60 controls with normal CSF amyloid beta, normal cognition, and no APOE epsilon 4 allele (average age 75 +/- 6 years). Results One hundred twenty-nine proteins (53%) were associated with aggregated amyloid beta. APOE epsilon 4 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 epsilon 4 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. Conclusions 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.
Filiaciones:
Konijnenberg, E:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, POB 7057, NL-1007 MB Amsterdam, Netherlands
Tijms, BM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, 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
Dobricic, V:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Bos, I:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, POB 7057, NL-1007 MB Amsterdam, Netherlands
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Vos, S:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Tsolaki, M:
AHEPA Univ Hosp, Dept Neurol 1, Macedonia Greece, Thessaloniki, Greece
Verhey, F:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Popp, J:
Univ Hosp Lausanne, Dept Psychiat, Lausanne, Switzerland
Martinez-Lage, P:
CITA Alzheimer Fdn, Ctr Res & Adv Therapies, Dept Neurol, San Sebastian, Spain
Vandenberghe, R:
Univ Hosp Leuven, Leuven, Belgium
Lleo, A:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Frolich, L:
Heidelberg Univ, Zentralinst Seel Gesundheit, Dept Geriatr Psychiat, Mannheim, Germany
Lovestone, S:
Univ Oxford, Dept Psychiat, Oxford, England
Janssen R&D, Beerse, Belgium
Streffer, J:
UCB Biopharma SPRL, Early Clin Neurol, Braine Lalleud, Belgium
Janssen R&D LLC, Beerse, Belgium
Bertram, L:
Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt, Lubeck, Germany
Imperial Coll London, Sch Publ Hlth, London, England
Univ Oslo, Dept Psychol, Oslo, Norway
Blennow, K:
Sahlgrens Univ Hosp, Inst Neurosci & Physiol, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden
Teunissen, CE:
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Neurochem Lab, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Biobank, Amsterdam, Netherlands
Veerhuis, R:
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Neurochem Lab, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Biobank, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Psychiat, Amsterdam UMC, Amsterdam, Netherlands
Smit, AB:
Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Mol & Cellular Neurobiol, Amsterdam, Netherlands
Scheltens, P:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, POB 7057, NL-1007 MB Amsterdam, Netherlands
Zetterberg, H:
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Neurochem Lab, Amsterdam, Netherlands
Vrije Univ Amsterdam, Dept Clin Chem, Amsterdam UMC, Biobank, Amsterdam, Netherlands
UCL Inst Neurol, Dept Mol Neurosci, London, England
UK Dementia Res Inst, London, England
Visser, PJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UMC, POB 7057, NL-1007 MB Amsterdam, Netherlands
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands
Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
Gold, Green Published
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