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Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain

Award Number: R01AG075728
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain - Movement is a volitional behavior linked to Alzheimer’s disease and related dementias (ADRD). Though many older adults show some degree of Alzheimer’s disease and related pathologies, the extent that these pathologies degrade movement varies. The same amount of Alzheimer’s disease and related pathologies may be related to rapid decline in one adult and little loss in another. An adult who maintains movement or has a slower rate of decline in the presence of Alzheimer’s disease and related pathologies manifests motor resilience. To promote motor resilience, it is crucial to identify risk factors or proteins that offset the negative effects of Alzheimer’s disease and related pathologies. Shared neural substrate underlies motor and cognitive resources that control movement. So, it’s not surprising that cognitive resilience proteins are related to motor resilience. This study will complement our ongoing discovery of resilience using deep omics in “cognitive” brain regions with deep omics in key “motor regions” to identify new genes and proteins that may provide motor and cognitive resilience. This study responds to NOT-AG-20-053. We selected 3 key motor tissues in which to identify motor resilience proteins that may offset the negative effects of pathologies of Alzheimer’s disease and related dementias (ADRD) and degeneration in motor systems. We will then test if some of these proteins also provide cognitive resilience. Compelling data support this study: 1) Alzheimer’s disease pathology in brainstem and spinal cord is related to a higher odds of dementia. 2) Large individual differences in degeneration of spinal motoneurons, nerve and muscle, highlight the need to measure their degeneration to isolate motor resilience. 3) Our systems biology and protein validation approach applied to RNAseq in dorsal lateral prefrontal cortex (DLPFC) identified cognitive resilience genes and proteins in prior work. 4) This approach can succeed in motor tissues as high quality RNAseq data, summarized as co-expression modules, was obtained from 3 key motor tissues (brain [SMA], spinal cord and muscle) from the same decedents. 5) As hypothesized, after isolating motor resilience, we identified proteins in DLPFC that provide resilience for motor or cognitive decline and some that provide resilience for both. Motor resilience manifests as slower motor decline. We will quantify Alzheimer’s disease and related pathologies in brain, brainstem, spinal cord, nerve and muscle to isolate motor resilience i.e., motor decline not explained by Alzheimer’s disease and related pathologies and degeneration. Aim 1 will apply a systems biology approach to transcriptome data from 3 key motor tissues (brain, spinal cord and muscle) to discover genes that may provide motor resilience. Aim 2 will verify these genes with SRM proteins and validate that these proteins are related to motor decline in an independent sample of adults. Aim 3 will test if motor resilience proteins also provide cognitive resilience and if aggregating multiple proteins into a person-specific index quantifies high and low resilience related to Alzheimer’s disease phenotypes. Aim 4 will test if resilience proteins link risk factors with motor and cognitive decline. Resilience proteins are high value targets for drug discovery to maintain motor and cognitive function despite the presence of untreatable Alzheimer’s disease and related pathologies. These data will also inform on mechanisms underlying motor and cognitive decline and risk factors which provide resilience.


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 = $1,256,142 )
2025	2025	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	4	12/19/2024	NON-COMPETING CONTINUATION	$1,256,142
														Subtotal = $1,256,142

Issue Date FY: 2024 ( Subtotal = $1,426,500 )
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	000	3	2/12/2024	NON-COMPETING CONTINUATION	$1,283,850
2024	2024	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Aging Research	001	3	6/10/2024	NON-COMPETING CONTINUATION	$142,650
														Subtotal = $1,426,500

Issue Date FY: 2023 ( Subtotal = $1,470,851 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Aging Research	000	2	2/6/2023	NON-COMPETING CONTINUATION	$1,470,851
														Subtotal = $1,470,851

Issue Date FY: 2022 ( Subtotal = $1,354,497 )
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Aging Research	000	1	3/31/2022	NEW	$1,354,497
														Subtotal = $1,354,497

Grand Total All Awards = $5,507,990

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Identifying resilience proteins in key motor tissues that drive motor and cognitive decline and offset the negative effects of ADRD pathologies within and outside the brain

Award Number: R01AG075728

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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