Transcriptional signatures of brain aging and Alzheimer’s disease: What are our rodent models telling us?

Abstract

Aging is the biggest risk factor for idiopathic Alzheimer’s disease (AD). Recently, the National Institutes of Health released AD research recommendations that include: appreciating normal brain aging, expanding data-driven research, using open-access resources, and evaluating experimental reproducibility. Transcriptome data sets for aging and AD in humans and animal models are available in NIH-curated, publically accessible databases. However, little work has been done to test for concordance among those molecular signatures. Here, we test the hypothesis that brain transcriptional profiles from animal models recapitulate those observed in the human condition. Raw transcriptional profile data from twenty-nine studies were analyzed to produce p-values and fold changes for young vs. aged or control vs. AD conditions. Concordance across profiles was assessed at three levels: (1) # of significant genes observed vs. # expected by chance; (2) proportion of significant genes showing directional agreement; (3) correlation among studies for magnitude of effect among significant genes. The highest concordance was found within subjects across brain regions. Normal brain aging was concordant across studies, brain regions, and species, despite profound differences in chronological aging among humans, rats and mice. Human studies of idiopathic AD were concordant across brain structures and studies, but were not concordant with the transcriptional profiles of transgenic AD mouse models. Further, the five transgenic AD mouse models that were assessed were not concordant with one another. These results suggest that normal brain aging is similar in humans and research animals, and that different transgenic AD model mice may reflect selected aspects of AD pathology.