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Genetic architecture of age of onset of amyloid positivity: Integrating imaging and genetic tools to identify novel drivers of disease

Award Number: K76AG088554
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/23/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Genetic architecture of age of onset of amyloid positivity: Integrating imaging and genetic tools to identify novel drivers of disease - ABSTRACT. Alzheimer's disease (AD) involves a long prodromal stage where β-amyloid (Aβ) plaques accumulate before clinical symptom onset. Yet, the molecular factors that underlie the striking heterogeneity in the onset, accumulation, and response to AD neuropathology are poorly understood. Advances in imaging genetics offer an opportunity to move the field towards precision interventions by deconvolving the clinical heterogeneity by using sensitive imaging biomarkers and genetics to nominate novel targets for intervention. Genome-wide association studies (GWAS) have identified 70+ genetic loci linked to AD, shedding light on disease mechanisms. However, traditional case/control designs are limited by clinical misdiagnosis. My prior work has leveraged imaging-derived traits as a more precise phenotype closer to disease biology in genetic studies. Recent advances in artificial intelligence (AI), computational imaging analysis, and harmonization allow us to extract quantitative features from images that humans cannot see at a scale that can facilitate well-powered GWAS with more precise traits. We will leverage one such advanced modeling algorithm to estimate the age of Aβ+ onset from 16,000+ harmonized Aβ positron emission tomography (PET) from the AD Sequencing Project-Phenotype Harmonization Consortium (Contact-PI: Dr. Timothy Hohman--primary mentor). Characterizing the genetic architecture of Aβ+ onset can provide insight into the AD cascade of our research participants decades before they joined our studies. Our initial work has shown that the age of Aβ+ onset varies significantly (40 to over 90 years) but is a heritable trait. Beyond APOE, in a subset of the cohort we propose here, we have found that genes involved in Aβ clearance pathways seem to influence age of Aβ+ onset. Additionally, biological sex appears to play a significant role. In this proposal, I will expand upon this preliminary work to characterize the association of established AD-risk loci with age of Aβ+ onset, identify novel genetic drivers of age of Aβ+ onset leveraging state-of-the-art genome-wide approaches, and identify sex-specific genetic drivers of age of Aβ+. We will use cutting-edge methods that allow for inclusion of admixed individuals (rather than traditional exclusionary approaches) and that account for sex as a biological variable. I will receive training from world experts in AI and advanced analyses of large-scale image datasets, cutting-edge genomic analyses, the neurobiology of aging and clinical geriatrics, and important career development skills for a successful physician-scientist career. This K76 research proposal – along with the parallel detailed training plan that expands upon my expertise in genetics and radiology– uniquely position me as a leader and expert at the intersection of imaging and genetics to lead the way in developing more precise treatment strategies in AD and related dementias.


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 = $243,000 )
2026	2026	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	000	4	5/14/2026	NON-COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Issue Date FY: 2025 ( Subtotal = $243,000 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	004	3	6/26/2025	NON-COMPETING CONTINUATION	$243,000
2025	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Aging Research	002	2	3/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$242,999
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	001	1	3/27/2025	NEW	-$242,999
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	1	1/15/2025	NEW	$0
2025	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	003	1	4/7/2025	NEW	$0
														Subtotal = $243,000

Issue Date FY: 2024 ( Subtotal = $243,000 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Aging Research	000	1	8/23/2024	NEW	$243,000
														Subtotal = $243,000

Grand Total All Awards = $729,000

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Genetic architecture of age of onset of amyloid positivity: Integrating imaging and genetic tools to identify novel drivers of disease

Award Number: K76AG088554

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/23/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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