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

Détails

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Etat: Public
Version: Final published version
Licence: CC BY-NC 4.0
ID Serval
serval:BIB_0AAA4F4517D4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.
Périodique
Brain
Auteur(s)
Tijms B.M., Gobom J., Reus L., Jansen I., Hong S., Dobricic V., Kilpert F., Ten Kate M., Barkhof F., Tsolaki M., Verhey FRJ, Popp J., Martinez-Lage P., Vandenberghe R., Lleó A., Molinuevo J.L., Engelborghs S., Bertram L., Lovestone S., Streffer J., Vos S., Bos I., Blennow K., Scheltens P., Teunissen C.E., Zetterberg H., Visser P.J.
Collaborateur(s)
Alzheimer's Disease Neuroimaging Initiative (ADNI)
ISSN
1460-2156 (Electronic)
ISSN-L
0006-8950
Statut éditorial
Publié
Date de publication
01/12/2020
Peer-reviewed
Oui
Volume
143
Numéro
12
Pages
3776-3792
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Résumé
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.
Mots-clé
Alzheimer’s disease, cerebrospinal fluid, proteomics, subtypes
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/01/2021 19:57
Dernière modification de la notice
30/04/2021 7:08
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