The shared genetic architecture of modifiable risk for Alzheimer's disease: a genomic structural equation modelling study
•There is high genetic overlap between Alzheimer's disease modifiable risk factors•Genetic overlap forms distinct clusters of risk factors sharing common aetiology•Shared genetics among risk factors may underpin multimorbidity or cognitive reserve•Alzheimer's disease is genetically distinc...
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| Published in | Neurobiology of aging Vol. 117; pp. 222 - 235 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.09.2022
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0197-4580 1558-1497 1558-1497 |
| DOI | 10.1016/j.neurobiolaging.2022.02.016 |
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| Abstract | •There is high genetic overlap between Alzheimer's disease modifiable risk factors•Genetic overlap forms distinct clusters of risk factors sharing common aetiology•Shared genetics among risk factors may underpin multimorbidity or cognitive reserve•Alzheimer's disease is genetically distinct from its modifiable risk factors•Education-related genetics may moderate pathways between dementia and risk factors
Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention. |
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| AbstractList | •There is high genetic overlap between Alzheimer's disease modifiable risk factors•Genetic overlap forms distinct clusters of risk factors sharing common aetiology•Shared genetics among risk factors may underpin multimorbidity or cognitive reserve•Alzheimer's disease is genetically distinct from its modifiable risk factors•Education-related genetics may moderate pathways between dementia and risk factors
Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention. Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention.Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention. Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain incompletely understood. We identified genome-wide association studies for AD and its major modifiable risk factors. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling. We identified complex networks of genetic overlap among AD risk factors, but AD itself was largely genetically distinct. The data were best explained by a bi-factor model, incorporating a Common Factor for AD risk, and 3 orthogonal sub-clusters of risk factors. Taken together, our findings suggest that there is extensive shared genetic architecture between AD modifiable risk factors, but this is largely independent of AD genetic pathways. Extensive genetic pleiotropy between risk factors may influence AD indirectly by decreasing cognitive reserve or increasing risk of multimorbidity, leading to poorer brain health. Further work to understand the biology reflected by this communality may provide novel mechanistic insights that could help to prioritise targets for dementia prevention. |
| Author | Mathlin, Georgina Noyce, Alastair J Dobson, Ruth Jacobs, Benjamin M Bhui, Kamaldeep S Marshall, Charles R Foote, Isabelle F Bothongo, Phazha LK Watson, Cameron J Korszun, Ania Waters, Sheena |
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| Keywords | EFA AD GWAS Risk factors Dementia prevention SNP Shared genetics LD SEM APOE Alzheimer's disease genomic SEM Dementia CFA |
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| Snippet | •There is high genetic overlap between Alzheimer's disease modifiable risk factors•Genetic overlap forms distinct clusters of risk factors sharing common... Targeting modifiable risk factors may help to prevent Alzheimer's disease (AD), but the pathways by which these risk factors influence AD risk remain... |
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| SubjectTerms | Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer's disease Dementia Dementia prevention Genetic Predisposition to Disease - genetics Genome-Wide Association Study genomic SEM Genomics Humans Latent Class Analysis Risk factors Shared genetics |
| Title | The shared genetic architecture of modifiable risk for Alzheimer's disease: a genomic structural equation modelling study |
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