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The Longitudinal Course of Imaging Biomarkers in People At Risk for Alzheimer’s Disease

Award Number: R01AG021155
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2004
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The Longitudinal Course of Imaging Biomarkers in People At Risk for Alzheimer’s Disease - PROJECT SUMMARY / ABSTRACT This project conducts longitudinal Alzheimer’s Disease (AD) biomarker imaging on participants in the Wisconsin Registry for Alzheimer’s Prevention, a midlife observational cohort that is risk-enriched for AD due to parental history of AD dementia. We have been conducting longitudinal amyloid positron emission tomography (PET) with [11C]PiB since 2009 and tau PET with [18F]MK-6240 since 2017 together with advanced MRI, CSF and now longitudinal plasma biomarkers. In the prior funding period we demonstrated that non-demented persons who are Amyloid positive (A+), and tau+ (T+) have been exhibiting cognitive decline since midlife; we developed computational methods to construe amyloid from a temporal standpoint, including individual estimates of A+ onset age and its duration; we found that A+ chronicity predicts cognitive decline and time to dementia—which is ~23 years, giving empirical support to an oft-cited heuristic; we were an early adopter of [18F]MK-6240 for tau PET imaging and delineated its imaging characteristics; we developed and applied cutting edge measures of vascular compromise in the brain with dynamic 4D flow imaging including novel ways for assessing vessel stiffness that is associated with amyloid. The overarching hypothesis of this renewal is that recontextualizing PET amyloid burden along its temporal dimension and anchoring our analyses to A+ onset age and/or its duration will explain heterogeneity in the expression of other biomarkers and cognitive decline. A secondary goal is to determine what can be learned from serial plasma markers of A and T and N (relative to A+ chronology). In Aim 1, anchored to amyloid onset age we will examine factors related to progression of other biomarkers including tau, and examine cognitive decline over a 15 yr period of observation. We will determine the characteristics associated with T+ onset and rate of change (using MK6240 PET) relative to A+ chronicity; we will identify those who are exhibiting disease resistance (i.e., T- in the presence of more chronic A+) and identify the modifiable and genetic factors associated with this biomarker pattern; we will also examine plasma and CSF markers of AD and related disorders. In Aim 2: We will examine conditional processes regarding the added influence of vascular MRI measures on cognitive decline in the presence of progressing AD proteinopathy and patterns of neurodegeneration. Finally, Aim 3 employs computational algorithms to create a joint spatiotemporal profile of amyloid tau and neurodegeneration enabling a joint estimate of disease burden and progression. Significance: This work will fill in the biomarker timeline from late-middle age, providing clarity on the temporal span of preclinical AD proteinopathy anchored to amyloid onset. This project has the potential to greatly improve individualized prognostic precision in view of overall known disease burden, to shed insight on characteristics of disease resistance, and inform prevention strategies.


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 = $3,356,853 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	001	19	6/18/2025	NON-COMPETING CONTINUATION	$274,028
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	000	19	3/13/2025	NON-COMPETING CONTINUATION	$3,082,825
														Subtotal = $3,356,853

Issue Date FY: 2024 ( Subtotal = $2,617,616 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	001	18	6/25/2024	NON-COMPETING CONTINUATION	$261,761
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	000	18	3/15/2024	NON-COMPETING CONTINUATION	$2,355,855
														Subtotal = $2,617,616

Issue Date FY: 2023 ( Subtotal = $2,617,616 )
2023	2023	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	001	17	3/21/2023	NON-COMPETING CONTINUATION	$2,617,616
2023	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	000	15	10/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,617,616

Issue Date FY: 2022 ( Subtotal = $2,631,491 )
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	001	16	7/16/2022	COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Aging Research	000	16	7/12/2022	COMPETING CONTINUATION	$2,631,491
														Subtotal = $2,631,491

Issue Date FY: 2020 ( Subtotal = $1,802,518 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	000	15	4/16/2020	NON-COMPETING CONTINUATION	$1,802,518
														Subtotal = $1,802,518

Issue Date FY: 2019 ( Subtotal = $1,907,243 )
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	000	14	4/22/2019	NON-COMPETING CONTINUATION	$1,527,464
2019	2019	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	001	14	4/29/2019	SUPPLEMENT FOR EXPANSION	$379,779
														Subtotal = $1,907,243

Issue Date FY: 2018 ( Subtotal = $1,531,723 )
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	001	13	8/31/2018	SUPPLEMENT FOR EXPANSION	$98,843
2018	2018	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	000	13	5/14/2018	NON-COMPETING CONTINUATION	$1,432,880
														Subtotal = $1,531,723

Issue Date FY: 2017 ( Subtotal = $1,437,140 )
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	001	12	6/23/2017	NON-COMPETING CONTINUATION	$143,714
2017	2017	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Aging Research	000	12	4/26/2017	NON-COMPETING CONTINUATION	$1,293,426
														Subtotal = $1,437,140

Issue Date FY: 2016 ( Subtotal = $1,441,399 )
2016	2016	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	11	8/31/2016	COMPETING CONTINUATION	$1,441,399
														Subtotal = $1,441,399

Issue Date FY: 2014 ( Subtotal = $520,255 )
2014	2014	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	10	2/21/2014	NON-COMPETING CONTINUATION	$520,255
														Subtotal = $520,255

Issue Date FY: 2013 ( Subtotal = $501,640 )
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	001	9	5/28/2013	NON-COMPETING CONTINUATION	$23,884
2013	2013	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	9	3/30/2013	NON-COMPETING CONTINUATION	$477,756
														Subtotal = $501,640

Issue Date FY: 2012 ( Subtotal = $557,231 )
2012	2012	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	8	2/17/2012	NON-COMPETING CONTINUATION	$557,231
														Subtotal = $557,231

Issue Date FY: 2011 ( Subtotal = $586,541 )
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	7	2/18/2011	NON-COMPETING CONTINUATION	$549,215
2011	2011	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	001	7	6/9/2011	NON-COMPETING CONTINUATION	$37,326
														Subtotal = $586,541

Issue Date FY: 2010 ( Subtotal = $605,457 )
2010	2010	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	002	6	3/3/2010	COMPETING CONTINUATION	$605,457
2010	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Aging Research	001	5	3/2/2010	SUPPLEMENT FOR EXPANSION	$0
2010	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Aging Research	000	5	3/1/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $605,457

Issue Date FY: 2009 ( Subtotal = $148,500 )
2009	2009	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 N PARK ST	MADISON	WI	53715	DANE	USA	Aging Research	000	5	7/8/2009	SUPPLEMENT FOR EXPANSION	$148,500
														Subtotal = $148,500

Issue Date FY: 2008 ( Subtotal = $239,162 )
2008	2008	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Aging Research	000	5	7/3/2008	NON-COMPETING CONTINUATION	$239,162
														Subtotal = $239,162

Issue Date FY: 2007 ( Subtotal = $244,347 )
2007	2007	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	21 NORTH PARK STREET	MADISON	WI	53715	DANE	USA	Aging Research	000	4	7/12/2007	NON-COMPETING CONTINUATION	$244,347
														Subtotal = $244,347

Issue Date FY: 2006 ( Subtotal = $281,079 )
2006	2006	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Aging Research	000	3	7/28/2006	NON-COMPETING CONTINUATION	$281,079
														Subtotal = $281,079

Issue Date FY: 2005 ( Subtotal = $289,333 )
2005	2005	UNIVERSITY OF WISCONSIN SYSTEM/BOARD OF REGENTS	750 UNIVERSITY AVENUE	MADISON	WI	53706	DANE	USA	Aging Research	000	2	7/22/2005	NON-COMPETING CONTINUATION	$289,333
														Subtotal = $289,333

Issue Date FY: 2004 ( Subtotal = $287,630 ) (Continued on the next page)
Grand Total All Awards = $23,604,774

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The Longitudinal Course of Imaging Biomarkers in People At Risk for Alzheimer’s Disease

Award Number: R01AG021155

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2004

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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