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- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 2. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 6. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 7. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 8. |
- Norberg, Joakim, et al.
(författare)
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Regional Differences in Effects of APOE epsilon 4 on Cognitive Impairment in Non-Demented Subjects
- 2011
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 32:2, s. 135-142
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Tidskriftsartikel (refereegranskat)abstract
- Background: The APOE epsilon 4 allele is a risk factor for Alzheimer's disease (AD). APOE epsilon 4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE epsilon 4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. Methods: Data from 16 centers across Europe were analyzed. Results: A north-south gradient in APOE epsilon 4 prevalence existed in the total sample (62.7% for APOE epsilon 4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE epsilon 4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. Conclusion: The APOE epsilon 4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE epsilon 4 allele and cognition is region dependent.
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| 9. |
- Mangialasche, Francesca, et al.
(författare)
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Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.
- 2013
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 273:6, s. 602-621
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects.Methods: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis.Results: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year.Conclusions: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma–tocopherols and tocotrienols–as indirect indicators of AD pathology, and the utility of a multimodality approach.
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| 10. |
- Damian, Marinella, et al.
(författare)
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Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study
- 2013
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 36:1-2, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e. g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE >= 28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (A beta(42), t-tau, APOE epsilon 4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings. Copyright (C) 2013 S. Karger AG, Basel
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