Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics

被引：106

作者：

Tijms, Betty M. ^{[1
]}

Gobom, Johan ^{[2
,3
]}

Reus, Lianne ^{[1
]}

Jansen, Iris ^{[1
]}

Hong, Shengjun ^{[4
,5
]}

Dobricic, Valerija ^{[4
,5
]}

Kilpert, Fabian ^{[4
,5
]}

ten Kate, Mara ^{[1
]}

Barkhof, Frederik ^{[6
,7
,8
]}

Tsolaki, Magda ^{[9
]}

Verhey, Frans R. J. ^{[10
]}

Popp, Julius ^{[11
,12
]}

Martinez-Lage, Pablo ^{[13
]}

Vandenberghe, Rik ^{[14
,15
]}

Lle, Alberto ^{[16
]}

Molinuevo, Jose Luis ^{[17
,18
,19
]}

Engelborghs, Sebastiaan ^{[20
,21
,22
]}

Bertram, Lars ^{[4
,5
]}

Lovestone, Simon ^{[23
,24
]}

Streffer, Johannes ^{[20
,25
]}

Vos, Stephanie ^{[10
]}

Bos, Isabelle ^{[1
,10
]}

Blennow, Kaj ^{[2
,3
]}

Scheltens, Philip ^{[1
]}

Teunissen, Charlotte E. ^{[26
]}

Zetterberg, Henrik ^{[2
,3
,27
,28
]}

Visser, Pieter Jelle ^{[1
,10
,29
]}

机构：

[1] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Dept Neurol, Amsterdam Neurosci,Amsterdam UM,Locat VUmc, Amsterdam, Netherlands

[2] Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden

[3] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Sahlgrenska Acad, Molndal, Sweden

[4] Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany

[5] Univ Lubeck, Inst Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Lubeck, Germany

[6] Vrije Univ Amsterdam, Dept Radiol & Nucl Med, Amsterdam UMC, Amsterdam Neurosci,Locat VUmc, Amsterdam, Netherlands

[7] UCL London, Inst Neurol, London, England

[8] UCL London, Inst Healthcare Engn, London, England

[9] AHEPA Univ Hosp, Dept Neurol 1, Thessaloniki, Greece

[10] Maastricht Univ, Alzheimer Ctr Limburg, Sch Mental Hlth & Neurosci, Maastricht, Netherlands

[11] Univ Hosp Lausanne, Lausanne, Switzerland

[12] Geneva Univ Hosp, Dept Psychiat, Geriatr Psychiat, Geneva, Switzerland

[13] Fdn CITA Alzheimer Fundazioa, San Sebastian, Spain

[14] Univ Hosp Leuven, Neurol Serv, Leuven, Belgium

[15] Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium

[16] Univ Autonoma Barcelona, IIB St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain

[17] Pasqual Maragall Fdn, Barcelonasseta Brain Res Ctr BBRC, Barcelona, Spain

[18] Hosp Clin Barcelona, Alzheimers Dis Unit, Barcelona, Spain

[19] Hosp Clin Barcelona, Other Cognit Disorders Unit, Barcelona, Spain

[20] Univ Antwerp, Reference Ctr Biol Markers Dementia BIODEM, Inst Born Bunge, Antwerp, Belgium

[21] UZ Brussel, Dept Neurol, Brussels, Belgium

[22] Vrije Univ Brussel VUB, Ctr Neurosci C4N, Brussels, Belgium

[23] Univ Oxford, Oxford, England

[24] Janssen R&D, Beerse, Belgium

[25] UCB Biopharma SPRL, Brain Lalleud, Belgium

[26] Amsterdam UMC, Dept Clin Chem, Neurochem Lab, Locat VUmc,Amsterdam Neurosci, Amsterdam, Netherlands

[27] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England

[28] UCL, UK Dementia Res Inst, London, England

[29] Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden

来源：

BRAIN | 2020年 / 143卷

基金：

美国国家卫生研究院; 加拿大健康研究院; 瑞典研究理事会; 英国医学研究理事会; 欧洲研究理事会;

关键词：

Alzheimer's disease; cerebrospinal fluid; proteomics; subtypes; MILD COGNITIVE IMPAIRMENT; C-I EXPRESSION; NATIONAL INSTITUTE; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; APOLIPOPROTEIN-C; BIOMARKER SIGNATURE; CSF BIOMARKERS; A-BETA; TAU;

D O I：

10.1093/brain/awaa325

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：3776 / 3792

页数：17

共 84 条

[1] Human apolipoprotein C-I expression in mice impairs learning and memory functions [J].