| 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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| 2. |
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| 3. |
- 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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| 4. |
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| 5. |
- Wightman, D. P., et al.
(författare)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Tidskriftsartikel (refereegranskat)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 6. |
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| 7. |
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| 8. |
- Jansen, I. E., et al.
(författare)
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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 404-413
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
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| 9. |
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| 10. |
- Witoelar, A, et al.
(författare)
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Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 18088-
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Tidskriftsartikel (refereegranskat)abstract
- A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.
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| 19. |
- Creese, B, et al.
(författare)
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Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer's disease
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 273-
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Tidskriftsartikel (refereegranskat)abstract
- Psychosis (delusions or hallucinations) in Alzheimer’s disease (AD + P) occurs in up to 50% of individuals and is associated with significantly worse clinical outcomes. Atypical antipsychotics, first developed for schizophrenia, are commonly used in AD + P, suggesting shared mechanisms. Despite this implication, little empirical research has been conducted to examine whether there are mechanistic similarities between AD + P and schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with AD + P. Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at ten GWAS p value thresholds (PT) in 3111 AD cases from 11 cohort studies characterized for psychosis using validated, standardized tools. Association between PRS and AD + P status was tested by logistic regression in each cohort individually and the results meta-analyzed. The schizophrenia PRS was associated with AD + P at an optimum PT of 0.01. The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.18-fold increased risk (95% CI: 1.06–1.3; p = 0.001). These new findings point towards psychosis in AD—and particularly delusions—sharing some genetic liability with schizophrenia and support a transdiagnostic view of psychotic symptoms across the lifespan.
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| 20. |
- Rodriguez-Porcel, F, et al.
(författare)
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Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations
- 2022
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Ingår i: Translational neurodegeneration. - : Springer Science and Business Media LLC. - 2047-9158. ; 11:1, s. 24-
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Tidskriftsartikel (refereegranskat)abstract
- The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.
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| 21. |
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| 22. |
- Rongve, Arvid, et al.
(författare)
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GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10 −8 ). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10 −6 . We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.
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| 23. |
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| 25. |
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| 28. |
- Aarsland, D, et al.
(författare)
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Frequency and case identification of dementia with Lewy bodies using the revised consensus criteria
- 2008
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 26:5, s. 445-452
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objective:</i> To find the proportion of dementia with Lewy bodies (DLB) in a referral cohort of patients with a first-time diagnosis of mild dementia. <i>Background:</i> The proportion of DLB among the dementia sufferers is not known and the clinical consensus criteria have low sensitivity. We employed the revised DLB criteria to study the proportion with DLB in a community sample of patients with mild dementia. <i>Methods:</i> From March 2005 to March 2007, we included 196 patients from referrals to all geriatric medicine, old age psychiatry and neurology outpatient clinics in Rogaland and Hordaland counties in Western Norway. Standardized clinical instruments and diagnostic criteria were employed. <i>Results:</i> 65% had Alzheimer dementia, 20% DLB (16% probable DLB), 5.6% vascular dementia, 5.6% Parkinson disease with dementia, 2.0% frontotemporal dementia and 1.5% alcoholic dementia. There were no significant differences in the proportion with DLB according to age bands and dementia severity groups. The revised criteria for a clinical diagnosis of DLB increased the proportion of probable DLB by 25% compared to the previous criteria. <i>Conclusion:</i> DLB is common in patients with mild dementia, and is the second most common type of dementia. The introduction of new clinical criteria for DLB leads to an increase in the proportion diagnosed with probable DLB.
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| 29. |
- Aarsland, D, et al.
(författare)
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[New diagnostic criteria for Alzheimer disease]
- 2011
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Ingår i: Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke. - : Norwegian Medical Association. - 0807-7096. ; 131:22, s. 2224-5
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Tidskriftsartikel (refereegranskat)
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| 30. |
- Auning, E, et al.
(författare)
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Early and presenting symptoms of dementia with lewy bodies
- 2011
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 32:3, s. 202-208
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background/Aims:</i> To explore the presenting and early symptoms of dementia with Lewy bodies (DLB). <i>Method:</i> Patients with mild dementia fulfilling diagnostic criteria for DLB (n = 61) and Alzheimer’s disease (AD) (n = 109) were recruited from outpatient dementia clinics in western Norway. At diagnosis, caregivers were asked which symptom had been the presenting symptom of dementia. <i>Results:</i> Caregivers reported that memory impairment was the most common presenting symptom in DLB (57%), followed by visual hallucinations (44%), depression (34%), problem solving difficulties (33%), gait problems (28%), and tremor/stiffness (25%). In contrast, 99% of AD carers reported impaired memory as a presenting symptom, whereas visual hallucinations were a presenting symptom in 3% of the AD cases. <i>Conclusion:</i> DLB should be suspected in predementia cases with visual hallucinations.
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| 38. |
- Chwiszczuk, L, et al.
(författare)
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Higher Frequency and Complexity of Sleep Disturbances in Dementia with Lewy Bodies as Compared to Alzheimer's Disease
- 2016
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Ingår i: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 16:3-4, s. 152-160
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Sleep disturbances (SDs) are common in patients with all forms of dementia. However, most studies focus on Alzheimer's disease (AD) and less is known about the prevalence and characteristics of SD in dementia with Lewy bodies (DLB). <b><i>Objective:</i></b> The aims of this cross-sectional study were: (1) to examine the frequency of SD in DLB versus AD; (2) to compare patients with and without SD with regard to relevant clinical variables, and (3) to investigate the associations between SD and medication use. <b><i>Methods:</i></b> Patients with a first-time diagnosis of probable or possible DLB or AD were selected from the Dementia Study of Western Norway and recruited from clinics for old age psychiatry from 2010 until the end of 2013. <b><i>Results:</i></b> In all, 123 (55.7%) subjects with dementia suffered from at least one SD. Insomnia was present in 77 (34.8%), and 34 (20.7%) patients had probable REM-sleep behaviour disorder (RBD). All SDs were also significantly more frequent in patients with DLB than in AD, and DLB patients also more often had several co-occurring SDs. The presence of any SD was associated with more neuropsychiatric symptoms, higher morbidity, more parkinsonian symptoms and excessive daytime sleepiness. Antiparkinsonian medication was used more often in RBD, restless leg syndrome (RLS) and periodic limb movements, and benzodiazepines were also common in RLS. <b><i>Conclusions:</i></b> Sleep problems are more common in DLB patients compared to AD, and are associated with more clinical impairment. DLB patients frequently have several sleep problems occurring simultaneously, which suggests a need for screening and accurate assessment of sleep in DLB.
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| 41. |
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| 44. |
- Oesterhus, R, et al.
(författare)
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Long-term mortality in a cohort of home-dwelling elderly with mild Alzheimer's disease and Lewy body dementia
- 2014
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 38:3-4, s. 161-169
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Objective:</i></b> To study mortality in subjects with mild dementia in Norway with a special focus on patients with Lewy body dementia (LBD) compared to Alzheimer's disease (AD). <b><i>Methods:</i></b> All referrals of mild dementia patients to dementia clinics in western Norway from March 2005 to March 2007 were included and followed until December 2012. Diagnoses were based on a comprehensive standardized assessment program. <b><i>Results:</i></b> Of 209 patients, 137 (66%) had AD and 53 (25%) had LBD. Dementia was associated with increased mortality (standardized mortality ratio = 1.8, AD 1.5, LBD 2.6). The median survival time was 6.2 years (95% CI 5.4-6.9). Predictors of mortality were age at diagnosis (HR 1.1 per year) and LBD diagnosis (HR 2.4). <b><i>Conclusion:</i></b> Dementia patients had an increased mortality, particularly those with LBD.
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| 45. |
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| 46. |
- Rongve, A, et al.
(författare)
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[Alzheimer's disease and genetics]
- 2013
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Ingår i: Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke. - : Norwegian Medical Association. - 0807-7096. ; 133:14, s. 1449-52
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Tidskriftsartikel (refereegranskat)
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| 47. |
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| 48. |
- Rongve, A, et al.
(författare)
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Core and suggestive symptoms of dementia with lewy bodies cluster in persons with mild dementia
- 2010
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 29:4, s. 317-324
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Tidskriftsartikel (refereegranskat)abstract
- <i>Objectives:</i> To explore how the core and suggestive symptoms of dementia with Lewy bodies (DLB) cluster in persons with newly diagnosed mild dementia, and whether they are associated with a particular pattern of cognitive impairment. <i>Method:</i> Persons with mild dementia (n = 139) were recruited from dementia clinics in western Norway. Symptoms were rated using standardized instruments. A 2-step cluster analysis was applied to classify persons into groups according to scores on scales for hallucinations, parkinsonism, fluctuations and REM sleep behaviour disorder (RBD). <i>Result:</i> Four distinct clusters were revealed: a ‘Lewy body dementia’ (LBD) cluster with high scores for hallucinations, parkinsonism and fluctuation, and a ‘non-LBD’ cluster with low scores on all DLB symptom scales. In addition, 2 clusters with high scores on either RBD or cognitive fluctuation scales emerged. Persons in the LBD cluster had lower scores for visuospatial cognitive abilities as compared to the non-LBD group (p = 0.002). <i>Conclusion:</i> Applying cluster analysis, we identified distinct subgroups in mild dementia based on symptoms such as hallucinations, parkinsonism and cognitive fluctuations. Our findings provide empirical support for diagnosing DLB. Visual hallucinations and motor parkinsonism might be the most distinguishing symptoms for DLB in mild dementia.
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