Wednesday, January 7, 2026 1/7/2026

From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

Award Number: P01AG066597
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging - Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition that is the most common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology associated with FTD is frontotemporal lobar degeneration due to transactive DNA/RNA binding protein of ~43 kD (TDP-43 (FTLD-TDP), and this is also the underlying pathology in the vast majority of patients who have co-occurring amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders as well as a critical force in age- related disorders such as limbic-predominant age-related TDP-43 encephalopathy (LATE). Since discovering a role for TDP-43 pathology in human disease, important progress has been made in experimental cellular and animal models of disease. However, the human brain has many unique properties associated with distinctly human clinical disorders that are not easily replicated in these experimental models. Major gaps in knowledge thus constrain the development of disease-modifying treatment trials. Among these is our limited knowledge of the pathophysiologic consequences of the accumulation and progression of abnormal TDP-43 at a molecular level. At a microscopic level, a major limitation is that most patients with accumulating TDP-43 have sporadic disease that can be identified reliably only at autopsy, although ~20% of cases have familial FTLD (fFTLD) with known pathology during life. We are limited at translating this knowledge to a macroscale level where FTLD- TDP pathology is manifested in humans with heterogeneous clinical features as diverse as emotional dysregulation and impaired language both with and without a motor disorder. Moreover, there is limited knowledge of the factors contributing to the highly varying rates of disease progression. In five novel, independent but synergistic Projects and five Cores that support each of the Projects, this unique, multidisciplinary, Program Project Grant (PPG) adopts the innovative perspective of investigating the TDP-43-associated breakdown of neural networks at molecular, microscopic and macroscale levels in humans. We hypothesize that our novel, well-integrated, network perspective will fill major gaps in knowledge by elucidating mechanistic insights into the pathophysiology of abnormal TDP-43 and the associated pattern of disease progression, and offer a fresh perspective on the identification of accumulating TDP-43 pathology during life and its longitudinal course. This proposal is consistent with the highest priorities for FTD at the 2019 Alzheimer’s Disease and Related Disorders (ADRD) summit. By focusing on disruption of neural networks at molecular, microscopic and macroscale levels of brain functioning, our multidisciplinary network approach will elucidate the pathophysiology and spread of abnormal TDP-43 in humans, and examine the consequences of TDP-43 pathology for clinical disease during life in dementia and aging using fresh approaches to improve our mechanistic understanding of TDP-43 pathology in humans while maintaining the highest level of scientific rigor and contributing to urgent clinical needs such as treatment trials.


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 = $3,215,718 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	6	12/31/2025	COMPETING CONTINUATION	$3,215,718
2026	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	12/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,215,718

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	4/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $2,479,031 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	5	5/17/2024	NON-COMPETING CONTINUATION	$2,479,031
														Subtotal = $2,479,031

Issue Date FY: 2023 ( Subtotal = $2,479,382 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	002	4	7/18/2023	NON-COMPETING CONTINUATION	$2,479,382
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	004	4	8/28/2023	NON-COMPETING CONTINUATION	$0
2023	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	3	5/3/2023	NON-COMPETING CONTINUATION	$0
2023	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	3	4/18/2023	NON-COMPETING CONTINUATION	$0
2023	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	003	3	8/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,479,382

Issue Date FY: 2022 ( Subtotal = $2,479,787 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	001	3	5/20/2022	NON-COMPETING CONTINUATION	$2,479,787
2022	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	2	2/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,479,787

Issue Date FY: 2021 ( Subtotal = $2,467,715 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	2	7/20/2021	NON-COMPETING CONTINUATION	$2,467,715
														Subtotal = $2,467,715

Issue Date FY: 2020 ( Subtotal = $2,436,318 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Aging Research	000	1	9/11/2020	NEW	$2,436,318
														Subtotal = $2,436,318

Grand Total All Awards = $15,557,951

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From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

Award Number: P01AG066597

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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