Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
Por:
Tijms, BM, Gobom, J, Reus, L, Jansen, I, Hong, SJ, Dobricic, V, Kilpert, F, ten Kate, M, Barkhof, F, Tsolaki, M, Verhey, FRJ, Popp, J, Martinez-Lage, P, Vandenberghe, R, Lle, A, Molinuevo, JL, Engelborghs, S, Bertram, L, Lovestone, S, Streffer, J, Vos, S, Bos, I, Blennow, K, Scheltens, P, Teunissen, CE, Zetterberg, H, Visser, PJ, Alzheimers Dis Neuroimaging Initia
Publicada:
1 dic 2020
Resumen:
Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n=127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P>0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P<0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P=0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P=0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
Filiaciones:
Tijms, BM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Gobom, J:
Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden
Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden
Reus, L:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Jansen, I:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Hong, SJ:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Dobricic, V:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Kilpert, F:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
ten Kate, M:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Barkhof, F:
Vrije Univ Amsterdam, Dept Radiol & Nucl Med, Amsterdam UMC, Amsterdam Neurosci,Locat VUmc, Amsterdam, Netherlands
UCL London, Inst Neurol, London, England
UCL London, Inst Healthcare Engn, London, England
Tsolaki, M:
AHEPA Univ Hosp, Dept Neurol 1, Thessaloniki, Greece
Verhey, FRJ:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, Netherlands
Popp, J:
Univ Hosp Lausanne, Lausanne, Switzerland
Geneva Univ Hosp, Dept Psychiat, Geriatr Psychiat, Geneva, 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
Lle, A:
Univ Autonoma Barcelona, IIB St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain
Molinuevo, JL:
Pasqual Maragall Fdn, Barcelonasseta 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
UZ Brussel, Dept Neurol, Brussels, Belgium
Vrije Univ Brussel VUB, Ctr Neurosci C4N, Brussels, Belgium
Bertram, L:
Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany
Lovestone, S:
Univ Oxford, Oxford, England
Janssen R&D, Beerse, Belgium
Streffer, J:
Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium
UCB Biopharma SPRL, Brain Lalleud, Belgium
Vos, S:
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, Netherlands
Bos, I:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, 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,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Teunissen, CE:
Amsterdam UMC, Dept Clin Chem, Neurochem Lab, Locat VUmc,Amsterdam Neurosci, Amsterdam, Netherlands
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, UK Dementia Res Inst, London, England
Visser, PJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands
Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, Netherlands
Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
Hybrid Gold, Green Published
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