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Identification of endophenotypes associated with Alzheimer’s disease progression in Hispanic population

Award Number: R21AG077501
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Identification of endophenotypes associated with Alzheimer’s disease progression in Hispanic population - Abstract Dementia is caused by a constellation of age-associated neurodegenerative diseases collectively termed Alzheimer’s disease and related dementias (ADRD). ADRDs impair individuals' ablity to correctly function and constitutes a major worldwide public health problem, with no effective treatments available. ADRDs affect people of all ethnicities, but Hispanics are especially affected by it. Hispanics have 1.5-fold higher risk of developing ADRD than non-Hispanic whites. ADRDs are complex phenotypes and their diagnosis often requires invasive measures. Therefore, identifying reliable noninvasive early ADRD biomarkers is a key topic to provide better early diagnosis and guide patient’s treatment. Toward this goal, this project aims to identify novel non-invasive endophenotypes using transcriptomic profiling in an existing cohort of Hispanics from the Maracaibo Aging Study (MAS) living in Maracaibo, Venezuela. The MAS, begun in 1998, has surveyed longitudinally genetic, environmental, and socioeconomic elements that may contribute to ADRD prevalence. The MAS project currently includes ~5000 elderly individuals (aged ≥55 yr) and a subset of 415 genetically related participants that have been extensively phenotyped, including complete MRI brain imaging and comprehensive cognitive assessment with a high ADRD prevalence (6.8%). Using a family-based design, we calculate that genetic factors account for 67% of the variability in disease risk. To identify novel ADRD and cognitive decline endophenotypes, we will construct a RNASeq library for 1000 MAS participants, and apply our ERV (Endophenotype Ranking Value) method. We will divided MAS participants into two equal subsets of 500 each for discovery and replication sets respectively coming from Santa Rosa and Santa Lucia communities in Venezuela. The discovery subset will include 122 ADRD cases defined by DSM-IVR criteria and, more importantly, a set of 243 1st- to 5th-degree biological relatives who are not currently suffering from dementia. We will contrast them with a set of 135 unaffected individuals (lacking known relatives with ADRD) to identify gene expression endophenotypes. Differences between these groups can only occur due to genetic correlation between ADRD risk and an endophenotype as identified by the ERV method taking into account covariates such as age, age at onset, sex and APOE locus status. Endophenotypes detected in the discovery set will be confirmed as biomarkers in a set of 250 ADRD cases and 250 unaffected controls using a linear mixed model and later annotated by means of a scientific literature review. We tested our approach's validity using existing data from our Genetics of Brain Structure Study where we identified strong associations between known the expression of candidate genes’ and dementia risk. We will apply the ERV method to the MAS gene expression data and predict that it will perform even better since the MAS population manifests higher ADRD prevalence. This project will serve as a stepping stone to further characterization of ADRD predisposition in Hispanics and our approach may identify potentially novel candidate genes that confer or protect against ADRD risk in this population. The expected results of this scientific proposal will be the necessary seeds for future scientific proposals that will further extend our findings.


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 = -$14 )
2026	2022	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Aging Research	000	1	1/8/2026	NEW	-$14
														Subtotal = -$14

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Aging Research	000	1	5/24/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $404,953 )
2022	2022	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Aging Research	001	1	8/2/2022	NEW	$0
2022	2022	UNIVERSITY OF TEXAS RIO GRANDE VALLEY, THE	1201 WEST UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Aging Research	000	1	7/22/2022	NEW	$404,953
														Subtotal = $404,953

Grand Total All Awards = $404,939

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Identification of endophenotypes associated with Alzheimer’s disease progression in Hispanic population

Award Number: R21AG077501

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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