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Leveraging high-throughput functional data for assessment of Alzheimer's risk

Award Number: R43AG084431
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Leveraging high-throughput functional data for assessment of Alzheimer's risk - PROJECT SUMMARY Alzheimer’s disease (AD) and AD-related dementias (ADRD) are irreversible, progressive brain disorders, and AD in particular is the sixth leading cause of death in the United States. Neurological decline begins up to two decades before cognitive symptoms are apparent in patients, highlighting the need for early risk assessment, screening, and treatment. Given the high heritability of AD/ADRDs, genetic testing has the potential to inform an individual’s risk. Although some common variants in APOE are known to modulate AD risk, the majority of genetic risk stems from rare variants, which are collectively common in the population but individually have little population data to support their classification. Thus, most variants in AD/ADRD risk variants are classified as medically inactionable variants of uncertain significance (VUS), precluding identification and precision management of high-risk individuals. To address the need for improved clinical interpretation of AD/ADRD risk genes, Constantiam Biosciences is developing MAVEvidence, an application that leverages recently-developed multiplexed assays of variant effect (MAVEs). MAVEs probe disease-relevant functions of thousands of protein variants in a single experiment and have proven useful for clinical interpretation of cardiovascular and cancer disease risk genes. Recently, the first MAVEs for AD/ADRD genes generated data for thousands of variants of the AD risk gene APP and the Lewy body dementia (LBD) risk gene SNCA. The data sets, however, are large and statistically complex, requiring rigorous analysis before they can be applied as evidence, and are thus largely inaccessible to clinical variant scientists. MAVEvidence brings several key innovations to the field of AD/ADRD gene variant interpretation, including a rigorous statistical analysis of MAVE data within a Bayesian framework and personalized, quantitative AD/ADRD risk assessment. MAVEvidence will be used by variant scientists at genetic testing companies and diagnostic laboratories to classify variants that would otherwise be VUS, thus enabling physicians and patients to make informed decisions about AD/ADRD screening and treatment. This Phase I SBIR proposal focuses on developing MAVEvidence for use by variant scientists to interpret variants in AD/ADRD risk genes. In Aim 1, we curate and validate data from all three published MAVEs for APP and one for SNCA. In Aim 2, we calibrate the odds of pathogenicity for each variant based on scores of known pathogenic and benign variants and then translate these odds to functional evidence that can be applied directly within existing variant interpretation frameworks. In Aim 3, we generate personalized quantitative measures of risk based on genotype by integrating MAVE data and population AD/ADRD incidence data with the goal of validating our model using biobank data. Successful completion of these aims will de-risk a planned Phase II focused on application to a broader set of AD/ADRD risk genes and development of a commercial-ready product.


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 = $0 )
2025	2024	CONSTANTIAM BIOSCIENCES INC	6306 GRAND SUMMIT CT	KATY	TX	77494	FORT BEND	USA	Aging Research	000	1	8/8/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $485,192 )
2024	2024	CONSTANTIAM BIOSCIENCES INC	6306 GRAND SUMMIT CT	KATY	TX	77494	FORT BEND	USA	Aging Research	000	1	9/17/2024	NEW	$485,192
														Subtotal = $485,192

Grand Total All Awards = $485,192

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Leveraging high-throughput functional data for assessment of Alzheimer's risk

Award Number: R43AG084431

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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