serval:BIB_0AAA4F4517D4
Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.
10.1093/brain/awaa325
000615920000034
33439986
Tijms
B.M.
author
Gobom
J.
author
Reus
L.
author
Jansen
I.
author
Hong
S.
author
Dobricic
V.
author
Kilpert
F.
author
Ten Kate
M.
author
Barkhof
F.
author
Tsolaki
M.
author
Verhey
FRJ
author
Popp
J.
author
Martinez-Lage
P.
author
Vandenberghe
R.
author
Lleó
A.
author
Molinuevo
J.L.
author
Engelborghs
S.
author
Bertram
L.
author
Lovestone
S.
author
Streffer
J.
author
Vos
S.
author
Bos
I.
author
Alzheimer's Disease Neuroimaging Initiative (ADNI)
contributor
Blennow
K.
author
Scheltens
P.
author
Teunissen
C.E.
author
Zetterberg
H.
author
Visser
P.J.
author
article
2020-12-01
Brain
1460-2156
0006-8950
journal
143
12
3776-3792
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.
Alzheimer’s disease
cerebrospinal fluid
proteomics
subtypes
eng
60_published
true
peer-reviewed
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
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