Harnessing the paradoxical phenotypes of APOE ɛ2 and APOE ɛ4 to identify genetic modifiers in Alzheimer's disease
| Autor: | Juan Botas, Ismael Al-Ramahi, Samantha Mota, Young Won Kim, Shirin Soleimani, Daniel M Konecki, Olivier Lichtarge, Stephen J. Wilson, Amanda Koire |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Heterozygote Candidate gene Drosophila models Apolipoprotein E2 Epidemiology Apolipoprotein E4 Disease Biology 03 medical and health sciences Cellular and Molecular Neuroscience late‐onset Alzheimer's disease 0302 clinical medicine Developmental Neuroscience Alzheimer Disease medicine Animals Humans paradoxical phenotypes Allele Gene Exome sequencing apolipoprotein E Genetics Health Policy Homozygote Neurodegeneration Brain Theoretical Article medicine.disease Phenotype Psychiatry and Mental health 030104 developmental biology Mutation Drosophila Neurology (clinical) Geriatrics and Gerontology 030217 neurology & neurosurgery |
| Zdroj: | Alzheimer's & Dementia |
| ISSN: | 1552-5279 1552-5260 |
| DOI: | 10.1002/alz.12240 |
| Popis: | The strongest genetic risk factor for idiopathic late‐onset Alzheimer's disease (LOAD) is apolipoprotein E (APOE) ɛ4, while the APOE ɛ2 allele is protective. However, there are paradoxical APOE ɛ4 carriers who remain disease‐free and APOE ɛ2 carriers with LOAD. We compared exomes of healthy APOE ɛ4 carriers and APOE ɛ2 Alzheimer's disease (AD) patients, prioritizing coding variants based on their predicted functional impact, and identified 216 genes with differential mutational load between these two populations. These candidate genes were significantly dysregulated in LOAD brains, and many modulated tau‐ or β42‐induced neurodegeneration in Drosophila. Variants in these genes were associated with AD risk, even in APOE ɛ3 homozygotes, showing robust predictive power for risk stratification. Network analyses revealed involvement of candidate genes in brain cell type‐specific pathways including synaptic biology, dendritic spine pruning and inflammation. These potential modifiers of LOAD may constitute novel biomarkers, provide potential therapeutic intervention avenues, and support applying this approach as larger whole exome sequencing cohorts become available. |
| Databáze: | OpenAIRE |
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