Prioritizing Alzheimer Disease Gene-Environment Studies Using MoTrPAC Cross-Species Tissue-Specific Exercise Response Transcriptomics

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with memory loss and impaired mental function. A defining feature of AD biology is the accumulation of amyloid plaques in the brain. While plaques are a major target for late-onset AD (LOAD) therapeutics, the resulting treatments do not cure LOAD and are only moderately effective in slowing progression. The challenges of developing effective LOAD therapies after the onset of disease underscore the need to identify modifiable risk factors that can be leveraged earlier in life to avoid onset or even after onset to slow progression and promote higher quality of life for both patients and their care givers. Several non-modifiable risk factors include increased age, female sex, genetics, and family history of AD. One modifiable factor associated with protection from LOAD is physical activity where exercise is associated with lower risk of developing LOAD. Several studies suggest that physical activity modifies genetic risk for LOAD and that this relationship can be statistically described in gene x environment (GxE) association studies. Most LOAD GxE studies are candidate variant or gene focused on APOE, the strongest independent LOAD genetic risk factor. With now ~75 genome-wide associated genetic variants/genomic regions, the majority of LOAD genetic risk has yet to be tested for modification by physical activity or other possible modifiable factors. Critical gaps in the field of AD research are to understand the molecular basis of how exercise exerts a neuroprotective effect, and how the genetic factors that influence AD risk are modified by physical activity. The molecular impact of physical activity, while difficult to study in humans, is now being systematically mapped in rats as part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC). MoTrPAC offers a public molecular map of the effects of induced exercise based on ‘omic data generated from 19 tissues harvested from 6-month old male and female rats that underwent up to 8 weeks of exercise training. We propose to leverage public cross-species transcriptomic MoTrPAC data to prioritize LOAD-associated genomic variants/regions for human GxE studies for LOAD and physical exercise in the diverse All of Us Research Program. We expect that upon the completion of this one-year project, we will have undertaken the most thorough examination of physical activity as a modifier of APOE risk in diverse populations as well as developed a MoTrPAC-informed pipeline to continue the work of identifying other genomic regions modified by exercise relevant to LOAD risk in other populations. Project Number: 1R03AG102041-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: DANA CRAWFORD (+1 co-PI) | Institution: CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OH | Award Amount: $78,500 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 MSOS-T (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11248171