Saturday, November 23, 2024 11/23/2024

Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

Award Number: R01AG072753
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract The etiology, mechanism and progression of Alzheimer’s Disease (AD), and the relationship of AD pathology to clinical manifestations, are not fully understood. Emerging studies suggest that inflammation and microglial activation is an important contributor to AD pathogenesis and progression. The association between tau and microglia is especially critical, since tau is most closely associated with AD. The conventionally accepted sequence of this interaction is that misfolded tau, which is pro-inflammatory, causes microglial activation, leading to dendritic pruning and eventually neuronal cell death. However, it is recently emerging that microglial activation can itself cause tau aggregation and subsequent propagation. Therefore the causality of these interactions is controversial, and requires much needed elucidation in humans in vivo. The goal of this proposal is to understand the interaction and causal sequencing between tau, neurodegeneration, microglia and systemic inflammation in governing the etiology and progression of human AD. This proposal involves a series of principled statistical and mathematical model-based tests that will uncover these relationships, for the first time, directly in patients. This proposal involves a new prospective longitudinal study of 100 AD spectrum patients acquiring brain MRI and PET imaging of activated microglia using a new generation TSPO ligand called DPA-713 and tau-PET imaging using a relatively novel ligand, MK6240. The same imaging protocol (MRI, DPA-713 and MK6240 PET) will be repeated at 18- and 36-month follow up time points. All subjects will have amyloid neuritic plaque density measured at baseline using florbetaben PET. Next this proposal involves developing and testing a model of microglial inflammation-tau interaction via mathematical models to determine whether regional microglia-mediated neuroinflammation measured by DPA-PET is higher in AD spectrum patients or in cognitively normal older adults; and whether regional microglial activation is predictable directly from tau and/or amyloid. Finally, this proposed research includes testing a network spread model of tau and microglia. Mounting animal data implicate a trans-neuronal transmission mechanism of tau through brain networks. Using a network diffusion model of disease spread, this proposal will further investigate the role of microglia in tau progression directly in humans. Since tau and microglia provide complementary signal about evolving pathology, this proposal will determine whether combining imaging studies that measure both biomarkers will result in a uniquely powerful and predictive test of AD progression. Given the rapidly evolving understanding of the role of microglia and systemic inflammation in dementias, the current proposal is timely, topical and necessary for advancing human dementia research. If successful, it will give the first validated spatiotemporal model of the causal interactions between pathology and neuroinflammation in AD, catalyzing future advances in prognostication and targeted anti-inflammatory 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: 2025 ( Subtotal = -$229,373 )
2025	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	4	11/8/2024	NON-COMPETING CONTINUATION	-$1,183,161
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	5	11/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$953,788
														Subtotal = -$229,373

Issue Date FY: 2024 ( Subtotal = $1,183,162 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	001	4	7/18/2024	NON-COMPETING CONTINUATION	$0
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Aging Research	000	4	7/15/2024	NON-COMPETING CONTINUATION	$1,183,162
														Subtotal = $1,183,162

Issue Date FY: 2023 ( Subtotal = $1,203,102 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	3	5/19/2023	NON-COMPETING CONTINUATION	$1,203,102
														Subtotal = $1,203,102

Issue Date FY: 2022 ( Subtotal = $1,319,736 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	2	5/16/2022	NON-COMPETING CONTINUATION	$1,319,736
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	2	6/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,319,736

Issue Date FY: 2021 ( Subtotal = $1,141,642 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	8/19/2021	NEW	$1,141,642
														Subtotal = $1,141,642

Grand Total All Awards = $4,618,269

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Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

Award Number: R01AG072753

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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