| 1. |
- de Rojas, I., et al.
(författare)
-
Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
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).
|
|
| 2. |
|
|
| 3. |
- Bellenguez, C, et al.
(författare)
-
New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
-
Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
-
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.
|
|
| 4. |
|
|
| 5. |
- Wightman, D. P., et al.
(författare)
-
A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
-
Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
-
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.
|
|
| 6. |
- Elvsashagen, T, et al.
(författare)
-
The genetic architecture of human brainstem structures and their involvement in common brain disorders
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4016-
-
Tidskriftsartikel (refereegranskat)abstract
- Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
|
|
| 7. |
- Goncalves-Pereira, M, et al.
(författare)
-
[Needs for Care and Service Use in Dementia: Baseline Assessment of Portuguese Participants in the Actifcare Cohort Study]
- 2019
-
Ingår i: Acta medica portuguesa. - : Ordem dos Medicos. - 1646-0758 .- 0870-399X. ; 32:5, s. 355-367
-
Tidskriftsartikel (refereegranskat)abstract
- Introdução: As pessoas com demência e os seus familiares deveriam ter acesso atempado a cuidados formais na comunidade (centros de dia, apoio domiciliário). O projecto EU-Actifcare investigou o acesso/utilização destes serviços em países europeus. Descrevemos a implementação do estudo de coorte e a avaliação inicial em Portugal, com foco nas necessidades de cuidados e recurso aos serviços.Material e Métodos: Selecionámos uma amostra de conveniência de 66 pessoas com diagnóstico de demência ligeira a moderada (residindo na comunidade sem cuidados formais relevantes) e respetivos familiares-cuidadores. A avaliação (clínico-funcional e social) incluiu os instrumentos Camberwell Assessment of Need for the Elderly e Resource Utilization in Dementia.Resultados: Identificámos necessidades não-cobertas dos doentes (média 1,1; DP = 1,7), principalmente de companhia (23% dos casos), sofrimento psicológico (20%) e atividades diárias (14%). Os familiares-cuidadores dedicavam 150 minutos/dia (mediana) à prestação de cuidados e 44% apresentavam necessidades não-cobertas de sofrimento psicológico. Quando havia problemas de acesso/utilização dos serviços de saúde e sociais na comunidade, estes estavam frequentemente relacionados com recusa ou desconhecimento de utentes/familiares.Discussão: A seleção dos participantes não foi fácil, pela especificidade dos critérios adotados. Não almejando representatividade nacional, recrutámos uma amostra típica de pessoas em estádios ligeiros a moderados de demência, em serviços e regiões diferentes. Nalguns casos, encontrámos necessidades não-cobertas e repercussões familiares que já justificariam respostas de serviços na comunidade, não fossem os problemas de acesso/utilização.Conclusão: Na área das demências, existem dificuldades no acesso atempado e utilização efectiva de cuidados formais, coexistindo com uma cobertura menor de necessidades específicas.
|
|
| 8. |
- Jansen, I. E., et al.
(författare)
-
Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 404-413
-
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.
|
|
| 9. |
|
|
| 10. |
|
|
