In vivo validation of late-onset Alzheimer's disease genetic risk factors
Sasner, M.; Preuss, C.; Pandey, R. S.; Uyar, A.; Garceau, D.; Kotredes, K. P.; Williams, H.; Oblak, A.; Lin, P. B.-C.; Perkins, B.; Soni, D. M.; Ingraham, C.; Gosselin, A. L.; Lamb, B. T.; Howell, G.; Carter, G. W.
Show abstract
Structured AbstractO_ST_ABSIntroductionC_ST_ABSGenome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimers disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. MethodsCandidate 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. ResultsWe 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. DiscussionThese results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease 96%
- Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer’s disease 96%
- Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy 96%
Similar papers in this journal
- Exploring the genetic heterogeneity of Alzheimer’s disease: Evidence for genetic subtypes 97%
- Brain and Blood Transcriptome-Wide Association Studies Identify Five Novel Genes Associated with Alzheimer’s Disease 96%
- Transcriptional and translational regulation of pathogenesis in Alzheimer's disease model mice 95%
Similar papers in this journal
- Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease 95%
- Immune receptor LAG3 regulates microglia function duringAlzheimer's disease 95%
- An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimers disease 94%
Similar papers in this journal
- Integrative Brain Transcriptome Analysis Links Complement Component 4 and HSPA2 to the APOE ε2 Protective Effect in Alzheimer Disease 97%
- N1-methylation of adenosine (m1A) in ND5 mRNA leads to complex I dysfunction in Alzheimer's disease 96%
- Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.