Dataset Information

Molecular subtypes of Alzheimer's disease.

ABSTRACT: Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid ? (A?) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that A? assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of A? species. These differences affect the physicochemical properties of A? assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. A?-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated A?. We found that brain homogenates from AD patients with different molecular profiles of A? are able to induce distinct patterns of A?-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of A? peptides into different A? seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.

SUBMITTER: Di Fede G

PROVIDER: S-EPMC5818536 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular subtypes of Alzheimer's disease.

Di Fede Giuseppe G Catania Marcella M Maderna Emanuela E Maderna Emanuela E Ghidoni Roberta R Benussi Luisa L Tonoli Elisa E Giaccone Giorgio G Moda Fabio F Paterlini Anna A Campagnani Ilaria I Sorrentino Stefano S Colombo Laura L Kubis Adriana A Bistaffa Edoardo E Ghetti Bernardino B Tagliavini Fabrizio F

Scientific reports 20180219 1

Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can cor ...[more]

PMID: 29459625

Similar Datasets

Project description: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.

Dataset Information

Molecular subtypes of Alzheimer's disease.

Publications

Molecular subtypes of Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure