Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.
Aged
Aged, 80 and over
Alzheimer Disease
/ cerebrospinal fluid
Amyloid Precursor Protein Secretases
/ cerebrospinal fluid
Amyloid beta-Peptides
/ cerebrospinal fluid
Aspartic Acid Endopeptidases
/ cerebrospinal fluid
Blood-Brain Barrier
/ pathology
Cluster Analysis
Cognitive Dysfunction
/ cerebrospinal fluid
Cohort Studies
Disease Progression
Female
Humans
Longitudinal Studies
Male
Mental Status and Dementia Tests
Middle Aged
Neuropsychological Tests
Peptide Fragments
/ cerebrospinal fluid
Proteomics
tau Proteins
/ cerebrospinal fluid
Alzheimer’s disease
cerebrospinal fluid
proteomics
subtypes
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 12 2020
01 12 2020
Historique:
received:
23
03
2020
revised:
03
08
2020
accepted:
06
08
2020
entrez:
13
1
2021
pubmed:
14
1
2021
medline:
2
3
2021
Statut:
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.
Identifiants
pubmed: 33439986
pii: 5986603
doi: 10.1093/brain/awaa325
pmc: PMC7805814
doi:
Substances chimiques
Amyloid beta-Peptides
0
MAPT protein, human
0
Peptide Fragments
0
amyloid beta-protein (1-42)
0
tau Proteins
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
BACE1 protein, human
EC 3.4.23.46
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3776-3792Subventions
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Informations de copyright
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.
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