Cerebrospinal fluid proteomics in patients with Alzheimer's disease reveals five molecular subtypes with distinct genetic risk profiles

被引：87

作者：

Tijms, Betty M. ^{[1
,2
]}

Vromen, Ellen M. ^{[1
,2
]}

Mjaavatten, Olav ^{[3
]}

Holstege, Henne ^{[1
,2
,4
]}

Reus, Lianne M. ^{[1
,2
,5
]}

van der Lee, Sven ^{[1
,2
,6
]}

Wesenhagen, Kirsten E. J. ^{[1
,2
]}

Lorenzini, Luigi ^{[7
,8
]}

Vermunt, Lisa ^{[2
,9
]}

Venkatraghavan, Vikram ^{[1
,2
]}

Tesi, Niccolo ^{[6
,10
]}

Tomassen, Jori ^{[1
,2
]}

den Braber, Anouk ^{[1
,2
,11
]}

Goossens, Julie ^{[12
]}

Vanmechelen, Eugeen ^{[12
]}

Barkhof, Frederik ^{[7
,13
,14
]}

Pijnenburg, Yolande A. L. ^{[1
,2
]}

van der Flier, Wiesje M. ^{[1
,2
]}

Teunissen, Charlotte E. ^{[2
,9
]}

Berven, Frode S. ^{[3
]}

Visser, Pieter Jelle ^{[1
,2
,15
,16
]}

机构：

[1] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC Locat VUmc, Amsterdam, Netherlands

[2] Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands

[3] Univ Bergen, Dept Biomed, Prote Unit, Bergen, Norway

[4] Vrije Univ Amsterdam, Dept Clin Genet, Amsterdam UMC locat VUmc, Amsterdam, Netherlands

[5] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA

[6] Vrije Univ Amsterdam, Genom Neurodegenerat Dis & Aging, Human Genet, Amsterdam UMC Locat VUmc, Amsterdam, Netherlands

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

[8] Amsterdam Neurosci, Neuroimaging, Amsterdam, Netherlands

[9] Vrije Univ Amsterdam, Dept Lab Med, Neurochem Lab, Amsterdam UMC locat VUmc, Amsterdam, Netherlands

[10] Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands

[11] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[12] ADx NeuroSci, Ghent, Belgium

[13] UCL, Queen Sq Inst Neurol, London, England

[14] UCL, Ctr Med Image Comp, London, England

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

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

来源：

NATURE AGING | 2024年 / 4卷 / 01期

基金：

荷兰研究理事会;

关键词：

AMYLOID-BETA; CHOROID-PLEXUS; TAU; MICROGLIA; BRAIN; TREM2; REST; PATHOLOGY; INSIGHTS; RECEPTOR;

D O I：

10.1038/s43587-023-00550-7

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine. Tijms et al. identify five molecular Alzheimer's disease subtypes typified by hyperplasticity, impaired immune activation, RNA metabolism, and choroid plexus or blood-brain barrier function. Subtypes may need tailored cures.

引用

页码：33 / 47

页数：24

共 106 条

[1] PICALM and Alzheimer's Disease: An Update and Perspectives [J].

Ando, Kunie ;

Nagaraj, Siranjeevi ;

Kucukali, Fahri ;

De Fisenne, Marie-Ange ;

Kosa, Andreea-Claudia ;

Doeraene, Emilie ;

Gutierrez, Lidia Lopez ;

Brion, Jean-Pierre ;

Leroy, Karelle .

CELLS, 2022, 11 (24)

[2] Pericytes regulate the blood-brain barrier [J].

Armulik, Annika ;

Genove, Guillem ;

Mae, Maarja ;

Nisancioglu, Maya H. ;

Wallgard, Elisabet ;

Niaudet, Colin ;

He, Liqun ;

Norlin, Jenny ;

Lindblom, Per ;

Strittmatter, Karin ;

Johansson, Bengt R. ;

Betsholtz, Christer .

NATURE, 2010, 468 (7323) :557-U231

[3] The many faces of REST oversee epigenetic programming of neuronal genes [J].

Ballas, N ;

Mandel, G .

CURRENT OPINION IN NEUROBIOLOGY, 2005, 15 (05) :500-506

[4] Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging [J].

Bell, Robert D. ;

Winkler, Ethan A. ;

Sagare, Abhay P. ;

Singh, Itender ;

LaRue, Barb ;

Deane, Rashid ;

Zlokovic, Berislav V. .

NEURON, 2010, 68 (03) :409-427

[5] New insights into the genetic etiology of Alzheimer's disease and related dementias [J].

Bellenguez, Celine ;

Kucukali, Fahri ;

Jansen, Iris E. ;

Kleineidam, Luca ;

Moreno-Grau, Sonia ;

Amin, Najaf ;

Naj, Adam C. ;

Campos-Martin, Rafael ;

Grenier-Boley, Benjamin ;

Andrade, Victor ;

Holmans, Peter A. ;

Boland, Anne ;

Damotte, Vincent ;

van der Lee, Sven J. ;

Costa, Marcos R. ;

Kuulasmaa, Teemu ;

Yang, Qiong ;

De Rojas, Itziar ;

Bis, Joshua C. ;

Yaqub, Amber ;

Prokic, Ivana ;

Chapuis, Julien ;

Ahmad, Shahzad ;

Giedraitis, Vilmantas ;

Aarsland, Dag ;

Garcia-Gonzalez, Pablo ;

Abdelnour, Carla ;

Alarcon-Martin, Emilio ;

Alcolea, Daniel ;

Alegret, Montserrat ;

Alvarez, Ignacio ;

Alvarez, Victoria ;

Armstrong, Nicola J. ;

Tsolaki, Anthoula ;

Antunez, Carmen ;

Appollonio, Ildebrando ;

Arcaro, Marina ;

Archetti, Silvana ;

Arias Pastor, Alfonso ;

Arosio, Beatrice ;

Athanasiu, Lavinia ;

Bailly, Henri ;

Banaj, Nerisa ;

Baquero, Miquel ;

Barral, Sandra ;

Beiser, Alexa ;

Pastor, Ana Belen ;

Below, Jennifer E. ;

Benchek, Penelope ;

Benussi, Luisa .

NATURE GENETICS, 2022, 54 (04) :412-436

[6] The role of ATP-binding cassette subfamily A in the etiology of Alzheimer's disease [J].

Bossaerts, Liene ;

Cacace, Rita ;

Van Broeckhoven, Christine .

MOLECULAR NEURODEGENERATION, 2022, 17 (01)

[7] Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease [J].

Busche, Marc Aurel ;

Eichhoff, Gerhard ;

Adelsberger, Helmuth ;

Abramowski, Dorothee ;

Wiederhold, Karl-Heinz ;

Haass, Christian ;

Staufenbiel, Matthias ;

Konnerth, Arthur ;

Garaschuk, Olga .

SCIENCE, 2008, 321 (5896) :1686-1689

[8] Transcriptomic profiling of sporadic Alzheimer's disease patients [J].

Caldwell, Andrew B. ;

Anantharaman, Balaji G. ;

Ramachandran, Srinivasan ;

Nguyen, Phuong ;

Liu, Qing ;

Trinh, Ivy ;

Galasko, Douglas R. ;

Desplats, Paula A. ;

Wagner, Steven L. ;

Subramaniam, Shankar .

MOLECULAR BRAIN, 2022, 15 (01)

[9] Dedifferentiation and neuronal repression define familial Alzheimer's disease [J].

Caldwell, Andrew B. ;

Liu, Qing ;

Schroth, Gary P. ;

Galasko, Douglas R. ;

Yuan, Shauna H. ;

Wagner, Steven L. ;

Subramaniam, Shankar .

SCIENCE ADVANCES, 2020, 6 (46)

[10] Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus [J].

Carna, Maria ;

Onyango, Isaac. G. ;

Katina, Stanislav ;

Holub, Dusan ;

Novotny, Jan Sebastian ;

Nezvedova, Marketa ;

Jha, Durga ;

Nedelska, Zuzana ;

Lacovich, Valentina ;

Vyvere, Thijs Vande ;

Houbrechts, Ruben ;

Garcia-Mansfield, Krystine ;

Sharma, Ritin ;

David-Dirgo, Victoria ;

Vyhnalek, Martin ;

Texlova, Katerina ;

Chaves, Hernan ;

Bakkar, Nadine ;

Pertierra, Lucia ;

Vinkler, Mojmir ;

Markova, Hana ;

Laczo, Jan ;

Sheardova, Katerina ;

Hortova-Kohoutkova, Marcela ;

Fric, Jan ;

Forte, Giancarlo ;

Kanovsky, Petr ;

Belaskova, Silvie ;

Damborsky, Jiri ;

Hort, Jakub ;

Seyfried, Nicholas. T. ;

Bowser, Robert ;

Sevlever, Gustavo ;

Rissman, Robert. A. ;

Smith, Richard. A. ;

Hajduch, Marian ;

Pirrotte, Patrick ;

Spacil, Zdenek ;

Dammer, Eric. B. ;

Limback-Stokin, Clara ;

Stokin, Gorazd. B. .

ALZHEIMERS & DEMENTIA, 2023, 19 (08) :3537-3554

← 1 2 3 4 5 6 7 8 9 10 →