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Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's Disease

Award Number: P01AG052350
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's Disease - OVERALL – PROJECT SUMMARY/ABSTRACT This is a continuing multi-disciplinary program on VASCULAR CONTRIBUTIONS TO DEMENTIA AND GENETIC RISK FACTORS FOR ALZHEIMER’S DISEASE with multiple projects, cores, institutions and 24 investigators from the Zilkha Neurogenetic Institute, Stevens Neuroimaging and Informatics Institute, Alzheimer’s Disease Research Center (ADRC), University of Southern California (USC), LA, CA; Washington University Knight ADRC, Dept. of Neurology, Washington University, St. Louis, MO; Huntington Medical Research Institutes, Pasadena, CA; Banner Alzheimer’s Institute and Mayo Clinic, AZ; Dept. of Psychology, UC Irvine; Dept. of Molecular Medicine, Scripps Research Institute ; and Centre for Clinical Brain Sciences, Univ. of Edinburgh, Scotland. The overall goal of the program is to test the ‘neurovascular hypothesis’ of AD and establish whether the neurovasculature has a major role in the pathogenesis of early cognitive decline, and therefore could be a key new therapeutic target to treat early cognitive impairment, dementia and early AD. The program includes continuing participation by accomplished investigators in all aspects of this research plan. The collective expertise of the investigators, overall environment, preliminary results, and experimental design for each of the projects and supporting cores produced considerable success of this program over the past 4 years. During this period we collected vast amounts of data, analyzed them and wrote an impressive number of high impact papers. Our renewal is concentrated on apolipoprotein E (APOE), the major genetic risk factor for AD. We propose longitudinal studies in APOE4 carriers (ε3/ε4; ε4/ε4) that are at high genetic risk for AD and develop early cerebrovascular changes including breakdown in the blood-brain barrier (BBB) relative to APOE3 homozygotes (ε3/ε3) that are at a lower risk for AD and develop slower cerebrovascular changes. We anticipate following 402 APOE4 carriers and 465 APOE3 homozygotes (ages 45-90) initially enrolled as cognitively unimpaired (CU, 75%) or with mild cognitive impairment (MCI, 25%). This includes 510 participants enrolled in the program during the initial P01 period, and 360 new participants to be recruited during the first 3 years of the renewal. In these APOE4 and APOE3 participants we will apply cutting-edge molecular and imaging methods to study the contribution of BBB/vascular dysfunction to preclinical cognitive decline, loss of brain connectivity, neurodegeneration, and longitudinal clinical progression along the continuum from CU to MCI, and MCI to dementia, in relation to Aβ and tau AD biomarker abnormalities (CSF, PET). Experimentally, we will study how BBB/vascular dysfunction relates to synaptic and neuronal dysfunction and behavior in APOE (knock-in)flox/flox (KIF) mice with and without apoE deletion from astrocytes and pericytes (key sources of BBB-associated apoE), and in these mice crossed with APP/PS1-21 and P301S tau lines, and treated with a cell-signaling activated protein C (APC) analog, 3K3A-APC. The results of this work may lead to new ways of thinking about pathogenesis, treatment and early prevention of cognitive impairment, dementia and AD for which we still do not have effective therapies.


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 = $0 )
2026	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	000	8	11/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $3,135,849 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	000	8	7/17/2025	NON-COMPETING CONTINUATION	$3,135,849
														Subtotal = $3,135,849

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	7	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $3,231,552 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	002	7	4/12/2023	NON-COMPETING CONTINUATION	$3,231,552
2023	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	001	6	12/9/2022	COMPETING CONTINUATION	$2,060,374
2023	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	5	12/9/2022	NON-COMPETING CONTINUATION	-$2,060,374
														Subtotal = $3,231,552

Issue Date FY: 2022 ( Subtotal = $3,246,490 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	001	6	5/13/2022	COMPETING CONTINUATION	$3,246,490
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	003	6	7/1/2022	COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	002	6	5/19/2022	COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	5	5/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,246,490

Issue Date FY: 2020 ( Subtotal = $2,424,168 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	5	6/10/2020	NON-COMPETING CONTINUATION	$2,424,168
														Subtotal = $2,424,168

Issue Date FY: 2019 ( Subtotal = $2,436,063 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	4	6/24/2019	NON-COMPETING CONTINUATION	$2,436,063
														Subtotal = $2,436,063

Issue Date FY: 2018 ( Subtotal = $2,436,063 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	3	7/20/2018	NON-COMPETING CONTINUATION	$2,436,063
														Subtotal = $2,436,063

Issue Date FY: 2017 ( Subtotal = $2,439,205 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	2	6/23/2017	NON-COMPETING CONTINUATION	$2,439,205
														Subtotal = $2,439,205

Issue Date FY: 2016 ( Subtotal = $2,585,455 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	1	9/17/2016	NEW	$2,585,455
														Subtotal = $2,585,455

Grand Total All Awards = $21,934,845

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Vascular Contributions to Dementia and Genetic Risk Factors for Alzheimer's Disease

Award Number: P01AG052350

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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