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

Award Number: R03AG102041
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/23/2025
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $78,500 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	1	9/22/2025	NEW	$78,500
														Subtotal = $78,500

Grand Total All Awards = $78,500

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

Award Number: R03AG102041

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/23/2025

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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