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Urban Air Pollution and Alzheimer's Disease: Risk, Heterogeneity, and Mechanisms

Award Number: P01AG055367
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Urban Air Pollution and Alzheimer's Disease: Risk, Heterogeneity, and Mechanisms - Our overarching goal is to further resolve the neurodegenerative role of traffic-related air pollutants (TRAP), a ubiquitous exposure in urban areas where most older Americans reside. Our recently published epidemiologic data showed strong association between elevated PM2.5 (particulate matter <2.5µm) and increased dementia risk in women >65 years, with a bias for ApoE4 homozygotes (JC Chen in Cacciottolo et al 2017, PMID 28140404). In this same report, experimental studies of female mice from the Finch-Sioutas Labs showed that exposure to nPM (a nano-sized subfraction of TRAP) was pro-amyloidogenic with an ApoE4 bias. Other changes include attrition of hippocampal CA1 neurites and myelin, which model selective damage in AD and cerebral ischemia. In a mouse stroke model, nPM exposure exacerbated cerebral ischemic damage (William Mack: Liu et al 2016, PMID 27071057). Differences by sex and ApoE alleles suggest sources of heterogeneity in human responses to TRAP. We propose four projects: epidemiological studies of two nationwide cohorts of women (Project 1, JC Chen: Women's Health Initiative Memory Studies; WHIMS) and men (Project 2, C Franz and W Kremen: Vietnam Era Twin Study of Aging, VETSA) and two experimental studies of air pollution exposure (Project 3, Finch: mouse models of aging and AD; Project 4 Wm Mack, chronic ceebral hypoperfusion). These projects address a common set of questions: (1) What is the AD risk imposed by TRAP and does the associated risk vary by sex, life stage, and APOE/other alleles? (2) What neurodegenerative changes are induced by TRAP and what is the resulting risk for early cognitive decline of AD? (3) Which brain pathways are most susceptible to TRAP neurotoxicity? (4) Do shared mechanisms (e.g., amyloidogenesis, cerebrovascular damage and hypoperfusion, and neuroinflammation) predispose to premature cognitive decline and an increased AD risk? Two supporting Cores provide population neuroinformatics, neuroimaging of blood-brain-barrier (BBB) and myelinated tracts, large-scale air pollution modeling and epidemiology, inhalation exposure assessment and neurotoxicology. Neuroimaging Core B1 provides human brain imaging harmonized across sites and mediation analyses (Projects1-2). B2 provides high-resolution imaging of BBB and tractography for mouse models (Projects 3-4). Core C Environmental Exposure and Neurotoxicology subcore C1 harmonizes population exposure estimates for WHIMS and VETSA (Projects1-2); C2 provides inhalation exposure of mice for studies of sex and ApoE allele responses (Project 3) and of chronic cerebral hypoperfusion (Project 4); C3 analyzes brain inflammatory protein responses to TRAP. For P01 integration, the Administrative Core builds on the infrastructure of AirPollBrain (led by Finch& Chen), a USC-funded collaborative network since 2010. Results of this program will advance understanding of TRAP contributions to AD risk and accelerated cognitive decline, and provide a rationale for preventive intervention in the environmental neurotoxicology of 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: 2026 ( Subtotal = -$68,450 )
2026	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	5	12/9/2025	NON-COMPETING CONTINUATION	-$68,450
														Subtotal = -$68,450

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Aging Research	000	5	7/2/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $2,264,495 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	5	7/27/2022	NON-COMPETING CONTINUATION	$2,264,495
														Subtotal = $2,264,495

Issue Date FY: 2021 ( Subtotal = $2,240,263 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	4	7/26/2021	NON-COMPETING CONTINUATION	$2,240,263
														Subtotal = $2,240,263

Issue Date FY: 2020 ( Subtotal = $2,308,593 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	3	7/15/2020	NON-COMPETING CONTINUATION	$2,308,593
														Subtotal = $2,308,593

Issue Date FY: 2019 ( Subtotal = $2,286,579 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	2	7/1/2019	NON-COMPETING CONTINUATION	$2,286,579
														Subtotal = $2,286,579

Issue Date FY: 2018 ( Subtotal = $2,431,964 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Aging Research	000	1	6/30/2018	NEW	$2,431,964
														Subtotal = $2,431,964

Grand Total All Awards = $11,463,444

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Urban Air Pollution and Alzheimer's Disease: Risk, Heterogeneity, and Mechanisms

Award Number: P01AG055367

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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