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Estrogens, Cardiometabolic Health, and Female Cognitive Aging

Award Number: P01AG071746
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Estrogens, Cardiometabolic Health, and Female Cognitive Aging - Overall Summary Loss of ovarian function at menopause is hypothesized to be a risk factor for Alzheimer’s disease and related dementias. Research in preclinical models indicates that estrogens are neuroprotective and can positively impact the cognitive aging trajectory. However, clinical data have been equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Variation in response to estrogen therapy in women suggests that pre-existing disease such as hypertension and metabolic syndrome can modulate mechanisms of estrogen action. These alterations may consequently reduce or reverse protections estrogens provide against cognitive decline, Alzheimer’s disease, and related dementias. The Program objective is to determine the impact of cardiometabolic status on the ability of exogenously administered estrogens to benefit the brain and cognition in an aging female rodent model. The overall hypothesis is that administration of estrogens in aging females will benefit the brain and cognition if initiated in healthy subjects, but will provide no benefits if initiated in the presence of cardiometabolic disease. Mechanisms by which these divergent effects occur are hypothesized to involve both alterations in mechanisms by which estrogens act directly on brain memory systems and mechanisms by which estrogens act on cardiometabolic systems, which in turn impact brain memory systems. Experiments under the four Projects will test this hypothesis. Project 1 will test the hypothesis that cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, will disrupt the ability of estrogens to regulate levels of ERα in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting impacts on memory. Project 2 will test the hypothesis that the presence of cardiometabolic disease impedes estrogen’s beneficial cognitive effects by blunting neurovascular coupling via endothelial nitric oxide synthase uncoupling, thus impairing the local network activity and synaptic plasticity required to preserve functional cortical circuits and therefore for cognition. Project 3 will test the hypothesis that cardiovascular disease alters the estrogen receptor profile, altering downstream molecular signaling pathways and attenuating its protective vascular effects and subsequent impact on cognition. Project 4 will test the hypothesis that insulin resistance caused by high fat diet impairs downstream signaling pathways necessary for estradiol’s beneficial influence on central regulation of glucose homeostasis, hippocampal long- term potentiation, and hippocampus-dependent cognitive function. The Administrative Core will provide leadership to the Program and ensure integration of all Program components. The Cardiometabolic and Hormones and Behavior Cores will provide critical consistencies in models and procedures to ensure scientific rigor and reproducibility of results across projects. Results will identify conditions under which estrogen treatment will (or will not) change the cognitive aging trajectory that could potentially reduce or delay age- related cognitive disease including Alzheimer’s disease and vascular dementia.


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: 2026 ( Subtotal = $2,799,973 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	5	3/26/2026	NON-COMPETING CONTINUATION	$2,799,973
														Subtotal = $2,799,973

Issue Date FY: 2025 ( Subtotal = $2,891,691 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	001	4	8/25/2025	NON-COMPETING CONTINUATION	$273,715
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	002	4	8/25/2025	SUPPLEMENT FOR EXPANSION	$66,644
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	4	1/31/2025	NON-COMPETING CONTINUATION	$2,551,332
														Subtotal = $2,891,691

Issue Date FY: 2024 ( Subtotal = $2,946,372 )
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	001	3	2/12/2024	NON-COMPETING CONTINUATION	$2,853,073
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	002	3	2/15/2024	SUPPLEMENT FOR EXPANSION	$79,971
2024	2024	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	2	12/14/2023	SUPPLEMENT FOR EXPANSION	$13,328
														Subtotal = $2,946,372

Issue Date FY: 2023 ( Subtotal = $2,860,477 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	2	1/31/2023	NON-COMPETING CONTINUATION	$2,860,477
														Subtotal = $2,860,477

Issue Date FY: 2022 ( Subtotal = $2,822,728 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Aging Research	000	1	2/24/2022	NEW	$2,822,728
														Subtotal = $2,822,728

Grand Total All Awards = $14,321,241

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Estrogens, Cardiometabolic Health, and Female Cognitive Aging

Award Number: P01AG071746

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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