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Understanding the role of menopause and estrogen receptor activation for Alzheimer's disease risk

Award Number: R01AG065209
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Understanding the role of menopause and estrogen receptor activation for Alzheimer's disease risk - PROJECT SUMMARY/ABSTRACT: Women have a higher prevalence of developing Alzheimer’s disease (AD) than men, which is believed to be associated with the drop in neuroprotective female sex hormone estrogen (E2) at menopause. Although E2 is well known for its neuroprotection, the underlying mechanisms are still largely unexplored, especially when it comes to the impact of menopausal E2 levels on the pathophysiology of AD. Clearly, a reason for this is the complexity of E2 signaling, which is mediated by brain area and cell-type specific estrogen receptor (ER) isoforms interacting with many signaling pathways, of which brain cholesterol metabolism is of major relevance to AD. Another reason is the controversies surrounding use of estrogenic compounds in menopausal hormone therapies (HT). Observational studies put forward an inverse association between HT use and risk of AD. However, several study limitations have raised important questions on the validity of these studies. To address this gap in knowledge, multidisciplinary efforts are needed: Large epidemiological studies based on high quality data on HT use, cardiometabolic disease history and other variables of pertinence including AD outcome are needed in combination with experimental studies acquired in models relevant to human AD and menopause. Our preliminary results suggest that the estrogen receptor beta (ERβ) has significant neuroprotective effects in an animal model relevant to human AD. Clear sex differences on AD pathology can be seen and the largest neuroprotective effect of ERβ is after induced menopause. In addition, our preliminary data supports ERβ as a node linking E2 signaling and brain cholesterol metabolism. In this 3-aim project, we will elaborate and expand on these data. We will unambiguously determine the neuroprotective contribution of E2 and ERβ in available and novel innovative models of human AD and menopause. In parallel, we will utilize high quality epidemiological data sets of over 88 000 postmenopausal women to study associations between HT use and AD outcome later in life. Importantly, we will have access to detailed data on HT use (including timing of initiation in relation to menopause), history of cardiovascular events, prevalence of cardiometabolic disease at baseline, genetic data and data on multiple potential confounding factors. We will link our data to national patient registers to identify AD as well as non-AD dementia diagnoses. In this way, we will accurately pinpoint the population-wide contribution of E2 and HT to AD and non-AD dementia risk. By combining the epidemiologic data with experimental studies we will also determine the effect of HT type, timing, genetic predispositions and contribution of specific ER isoforms and brain cholesterol metabolism on markers of AD. We also have the possibility to validate our data in postmortem AD brains. Overall, the combined expertise of our research team allows us to compare data acquired across different epidemiologic and experimental data sets to accurately determine the contribution of estrogenic neuroprotection to the sex differences observed in AD, which will contribute to better informed recommendations for HT use and evaluation of ERβ as a possible clinical target to combat AD.


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 = $0 )
2025	2023	KAROLINSKA INSTITUTET	NOBELS VAG 6	SOLNA				SWE	Aging Research	000	4	10/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	KAROLINSKA INSTITUTET	NOBELS VAG 6	SOLNA				SWE	Aging Research	000	4	10/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $359,398 )
2023	2023	KAROLINSKA INST	NOBELS VAG 6	SOLNA				SWE	Aging Research	000	4	8/11/2023	NON-COMPETING CONTINUATION	$359,398
														Subtotal = $359,398

Issue Date FY: 2022 ( Subtotal = $450,076 )
2022	2022	KAROLINSKA INST	NOBELS VAG 6	SOLNA				SWE	Aging Research	000	3	6/22/2022	NON-COMPETING CONTINUATION	$450,076
														Subtotal = $450,076

Issue Date FY: 2021 ( Subtotal = $469,300 )
2021	2021	KAROLINSKA INST	NOBELS VAG 6	SOLNA	STOCKHOLM			SWE	Aging Research	000	2	7/16/2021	NON-COMPETING CONTINUATION	$469,300
														Subtotal = $469,300

Issue Date FY: 2020 ( Subtotal = $475,973 )
2020	2020	KAROLINSKA INST	NOBELS VAG 6	SOLNA	STOCKHOLM	171 65		SWE	Aging Research	000	1	9/16/2020	NEW	$475,973
														Subtotal = $475,973

Grand Total All Awards = $1,754,747

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Understanding the role of menopause and estrogen receptor activation for Alzheimer's disease risk

Award Number: R01AG065209

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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