AI Article Synopsis
- Genome-wide studies have found over 70 genetic loci linked to late-onset Alzheimer's disease, but few have been thoroughly tested for their role in the disease.
- Researchers used a LOAD-sensitive mouse model to evaluate 11 potential genetic variants, analyzing their effects on brain gene expression at different ages.
- The findings reveal similarities between the genetic models and human Alzheimer's gene patterns, suggesting these models could be useful for developing targeted treatments.
Article Abstract
Introduction: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action.
Methods: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE4 and Trem2*R47H. Potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts.
Results: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes.
Discussion: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10769393 | PMC |
| http://dx.doi.org/10.1101/2023.12.21.572849 | DOI Listing |
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