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Disease pathways in the population determined by amyloid, tau, and neurodegeneration imaging biomarkers

Award Number: R37AG011378
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1993
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Disease pathways in the population determined by amyloid, tau, and neurodegeneration imaging biomarkers - PROJECT SUMMARY / ABSTRACT In 2010 we proposed, and in 2013 revised, a hypothetical model of the temporal evolution of biomarkers and clinical symptoms for individuals in the Alzheimer’s disease (AD) pathway. The biomarker model is based on a hypothesized cause and effect sequence which can be summarized as: amyloidosis (A), promotes tauopathy (T), which promotes neurodegeneration (N), which is the proximate cause of clinical symptoms (C). For simplicity, we use this ATNC notation: A T  N  C. The current cycle of AG011378 was designed to test aspects of this model that were testable using imaging; however, a major missing element when the current cycle AG011378 began in 2013 was a method to measure fibrillar tau deposits with imaging. Tau PET has recently become available and, consequently for the first time, imaging biomarkers exist to ascertain three of the most important pathologic features of AD: amyloid, tau and neurodegeneration. An important insight gained from the current cycle of AG011378 was that modeling AD biomarkers on the assumption that AD is the only pathological process present in the general aging population is conceptually flawed. We argue that biomarker modeling within the general aging population should accommodate at least three broad groups based on currently available biomarkers: (1) individuals with no biomarker abnormalities whose future biomarker profiles are unknown; (2) individuals along the Alzheimer’s continuum; and (3) a heterogeneous group with primarily suspected non-AD pathologies (SNAP). Our aims in this renewal are based on modeling longitudinal amyloid PET (A), tau PET (T), and MRI (N) biomarkers. The overarching goals of the renewal are to empirically evaluate our hypothetical model of AD biomarkers and to create complementary imaging biomarker models for individuals who are not in the Alzheimer’s continuum. Our specific aims are: Aim 1. To model the sequence of biomarker and clinical transitions over time across multiple pathways. Aim 1 employs hidden Markov models. 1a) To model the sequence of biomarker and clinical transitions in the Alzheimer’s continuum, 1b) To model the sequence of biomarker and clinical transitions in SNAP pathways. Aim 2. To model continuous biomarker and clinical trajectories over time across multiple pathways. Aim 2 analyses employ non-linear latent class mixed models. 2a) To model biomarker and clinical trajectories in the Alzheimer’s continuum, 2b) To model biomarker and clinical trajectories in SNAP pathways. Aim 3. To formulate mechanistic inferences about biomarker and clinical changes over time across multiple pathways. 3a) inferences in the Alzheimer’s continuum, 3b) inferences in SNAP pathways. Aim 4: To establish temporal ordering of topographic spread of A, T, and N within each modality, across imaging modalities, and establish how these temporal orderings relate to cognitive impairment within (4a) the Alzheimer’s continuum and (4b) the SNAP pathways. Aim 4 uses a conditional probability approach.


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 = $785,776 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	34	5/7/2026	NON-COMPETING CONTINUATION	$785,776
														Subtotal = $785,776

Issue Date FY: 2025 ( Subtotal = $770,061 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	33	6/20/2025	NON-COMPETING CONTINUATION	$62,861
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	33	4/24/2025	NON-COMPETING CONTINUATION	$707,200
														Subtotal = $770,061

Issue Date FY: 2024 ( Subtotal = $785,776 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	32	5/7/2024	NON-COMPETING CONTINUATION	$785,776
2024	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	30	4/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $785,776

Issue Date FY: 2023 ( Subtotal = $801,126 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	31	6/30/2023	EXTENSION WITH OR WITHOUT FUNDS	$801,126
														Subtotal = $801,126

Issue Date FY: 2022 ( Subtotal = $732,693 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	30	5/6/2022	NON-COMPETING CONTINUATION	$732,693
														Subtotal = $732,693

Issue Date FY: 2021 ( Subtotal = $732,693 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	29	5/5/2021	NON-COMPETING CONTINUATION	$732,693
														Subtotal = $732,693

Issue Date FY: 2020 ( Subtotal = $732,693 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	28	5/14/2020	NON-COMPETING CONTINUATION	$732,693
														Subtotal = $732,693

Issue Date FY: 2019 ( Subtotal = $778,405 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	27	5/22/2019	NON-COMPETING CONTINUATION	$732,693
2019	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	26	5/6/2019	COMPETING CONTINUATION	$45,712
2019	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	26	10/23/2018	COMPETING CONTINUATION	$0
														Subtotal = $778,405

Issue Date FY: 2018 ( Subtotal = $732,693 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	26	9/5/2018	COMPETING CONTINUATION	$732,693
														Subtotal = $732,693

Grand Total All Awards = $6,851,916

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Disease pathways in the population determined by amyloid, tau, and neurodegeneration imaging biomarkers

Award Number: R37AG011378

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/1993

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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