| 1. |
- Hong, S. J., et al.
(författare)
-
TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
-
Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
|
|
| 2. |
- Tijms, B. M., et al.
(författare)
-
Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics
- 2020
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143, s. 3776-3792
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Lovestone, S., et al.
(författare)
-
The European medical information framework: A novel ecosystem for sharing healthcare data across Europe
- 2020
-
Ingår i: Learning Health Systems. - : Wiley. - 2379-6146. ; 4:2
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction The European medical information framework (EMIF) was an Innovative Medicines Initiative project jointly supported by the European Union and the European Federation of Pharmaceutical Industries and Associations, that generated a common technology and governance framework to identify, assess and (re)use healthcare data, to facilitate real-world data research. The objectives of EMIF included providing a unified platform to support a wide range of studies within two verification programmes-Alzheimer's disease (EMIF-AD), and metabolic consequences of obesity (EMIF-MET). Methods The EMIF platform was built around two main data-types: electronic health record data and research cohort data, and the platform architecture composed of a set of tools designed to enable data discovery and characterisation. This included the EMIF catalogue, which allowed users to find relevant data sources, including the data-types collected. Data harmonisation via a common data model were central to the project especially for population data sources. EMIF also developed an ethical code of practice to ensure data protection, patient confidentiality and compliance with the European Data Protection Directive, and GDPR. Results Currently 18 population-based disease agnostic and 60 cohort-based Alzheimer's data partners from across 14 countries are contained within the catalogue, and this will continue to expand. The work conducted in EMIF-AD and EMIF-MET includes standardizing cohorts, summarising baseline characteristics of patients, developing diagnostic algorithms, epidemiological studies, identifying and validating novel biomarkers and selecting potential patient samples for pharmacological intervention. Conclusions EMIF was designed to provide a sustainable model as demonstrated by the sustainability plans for EMIF-AD. Although network-wide studies using EMIF were not conducted during this project to evaluate its sustainability, learning from EMIF will be used in the follow-on IMI-2 project, European Health Data and Evidence Network (EHDEN). Furthermore, EMIF has facilitated collaborations between partners and continues to promote a wider adoption of principles, technology and architecture through some of its continued work.
|
|
| 4. |
- Shi, Liu, et al.
(författare)
-
Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
-
Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
|
|
| 5. |
- Shi, Liu, et al.
(författare)
-
Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
-
Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
|
|
| 6. |
- Tijms, B. M., et al.
(författare)
-
CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals
- 2021
-
Ingår i: Proteomes. - : MDPI AG. - 2227-7382. ; 9:3
-
Tidskriftsartikel (refereegranskat)abstract
- We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p(181)-tau and amyloid beta 1-42 (A beta 42) CSF analysis showed that in the hyperplasticity subtype p(181)-tau increased (beta = 2.6 pg/mL per year, p = 0.01) and A beta 42 decreased over time (beta = -4.4 pg/mL per year, p = 0.03), in the innate immune activation subtype p(181)-tau increased (beta = 3.1 pg/mL per year, p = 0.01) while in the blood-brain barrier dysfunction subtype A beta 42 decreased (beta = -3.7 pg/mL per year, p = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
|
|
| 7. |
- Westwood, Sarah, et al.
(författare)
-
Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort
- 2020
-
Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 74:1, s. 213-225
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
|
|
| 8. |
- Konijnenberg, E., et al.
(författare)
-
APOE ϵ4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease
- 2020
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer's disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ϵ4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ϵ4 genotype. Methods: We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ϵ4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ϵ4 allele (average age 75 ± 6 years). Results: One hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ϵ4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ϵ4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility. Conclusions: These results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment. © 2020 The Author(s).
|
|
| 9. |
- Xu, Jin, et al.
(författare)
-
Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
- 2021
-
Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 9:11
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
|
|
| 10. |
- Hong, Shengjun, et al.
(författare)
-
Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
- 2020
-
Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
|
|
