| 1. |
- 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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| 3. |
- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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| 5. |
- Scott, G. D., et al.
(författare)
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Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium
- 2022
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.
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| 6. |
- Guerreiro, R., et al.
(författare)
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Heritability and genetic variance of dementia with Lewy bodies
- 2019
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 127, s. 492-501
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Tidskriftsartikel (refereegranskat)abstract
- Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.
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| 7. |
- Guerreiro, R., et al.
(författare)
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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
- 2018
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Ingår i: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74
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Tidskriftsartikel (refereegranskat)abstract
- Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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| 8. |
- Wolzak, K., et al.
(författare)
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Protein disulfide isomerases as CSF biomarkers for the neuronal response to tau pathology
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3563-3574
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionCerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation. MethodsWe employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF-AD MBD, n = 310; PRIDE, n = 771). ResultsFirst, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD). HighlightsNeuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro.PDIA1 is secreted upon tau aggregation in neurons in vitro.PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF.PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls.PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients.
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| 9. |
- Orme, T., et al.
(författare)
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Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- 2020
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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| 10. |
- Van Loenhoud, A. C., et al.
(författare)
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High occurrence of transportation and logistics occupations among vascular dementia patients : An observational study
- 2019
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Growing evidence suggests a role of occupation in the emergence and manifestation of dementia. Occupations are often defined by complexity level, although working environments and activities differ in several other important ways. We aimed to capture the multi-faceted nature of occupation through its measurement as a qualitative (instead of a quantitative) variable and explored its relationship with different types of dementia. Methods: We collected occupational information of 2121 dementia patients with various suspected etiologies from the Amsterdam Dementia Cohort (age 67 ± 8, 57% male; MMSE 21 ± 5). Our final sample included individuals with Alzheimer's disease (AD) dementia (n = 1467), frontotemporal dementia (n = 281), vascular dementia (n = 98), Lewy body disease (n = 174), and progressive supranuclear palsy/corticobasal degeneration (n = 101). Within the AD group, we used neuropsychological data to further characterize patients by clinical phenotypes. All participants were categorized into 1 of 11 occupational classes, across which we evaluated the distribution of dementia (sub)types with χ 2 analyses. We gained further insight into occupation-dementia relationships through post hoc logistic regressions that included various demographic and health characteristics as explanatory variables. Results: There were significant differences in the distribution of dementia types across occupation groups (χ 2 = 85.87, p <.001). Vascular dementia was relatively common in the Transportation/Logistics sector, and higher vascular risk factors partly explained this relationship. AD occurred less in Transportation/Logistics and more in Health Care/Welfare occupations, which related to a higher/lower percentage of males. We found no relationships between occupational classes and clinical phenotypes of AD (χ 2 = 53.65, n.s.). Conclusions: Relationships between occupation and dementia seem to exist beyond the complexity level, which offers new opportunities for disease prevention and improvement of occupational health policy.
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