ELUCIDATING SEX-SPECIFIC RISK FOR ALZHEIMER'S DISEASE THROUGH STATE-OF-THE-ART GENETICS AND MULTI-OMICS - A…

Assistance award details

Assistance award identifier

ASST_NON_R00AG075238_075

FAIN

R00AG075238

Recipient

WASHINGTON UNIVERSITY, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$832,971

Period

Sep 1, 2022 – Aug 31, 2026

Fiscal year

2024

Place of performance state

MO

Source file

FY2024_All_Assistance_Full_20261006.zip

Description

ELUCIDATING SEX-SPECIFIC RISK FOR ALZHEIMER'S DISEASE THROUGH STATE-OF-THE-ART GENETICS AND MULTI-OMICS - ABSTRACT ALZHEIMER’S DISEASE (AD) MANIFESTS ITSELF DIFFERENTLY ACROSS MEN AND WOMEN, BUT THE GENETIC AND MOLECULAR FACTORS THAT DRIVE THIS REMAIN LARGELY ELUSIVE. AD IS THE MOST COMMON CAUSE OF DEMENTIA, AFFECTING OVER 5 MILLION PEOPLE IN THE USA ALONE, AND TILL TODAY REMAINS ESSENTIALLY UNTREATABLE. BECAUSE AD HAS A STRONG GENETIC COMPONENT, WITH INHERITANCE ESTIMATES BETWEEN 50-80%, STUDYING THE GENETICS OF AD CAN IMPORTANTLY AID THE DISCOVERY OF NOVEL DRUG TARGETS. HOWEVER, EVIDENCE FROM VARIOUS LINES OF RESEARCH SUGGESTS THAT SEX DIFFERENCES ARE AN INTEGRAL PART OF AD. IT IS THEREFORE CRUCIAL TO STUDY THE GENETICS OF AD IN A SEX-SPECIFIC MANNER, AS THIS WILL HELP THE FIELD GAIN IMPORTANT INSIGHTS INTO DISEASE PATHOPHYSIOLOGY, IDENTIFY NOVEL SEX-SPECIFIC RISK FACTORS RELEVANT TO PERSONALIZED GENETIC MEDICINE, AND UNCOVER POTENTIAL NEW AD DRUG TARGETS THAT MAY BENEFIT BOTH SEXES. TO DATE, SURPRISINGLY FEW SEX-SPECIFIC VARIANTS/GENES HAVE BEEN IDENTIFIED, WHICH WE HYPOTHESIZE IS BECAUSE PRIOR STUDIES WERE FACED WITH SEVERAL OBSTACLES SUCH AS DATA LIMITATIONS AND UNEXPLORED RESEARCH AVENUES. THIS PROJECT PROPOSES TO USE BIG DATA TOGETHER WITH STATE-OF-THE-ART APPROACHES IN ORDER TO LEVERAGE ESTABLISHED SEX DIFFERENCES IN AD AS A MEANS OF ELUCIDATING NOVEL AD RISK GENES. AIM 1 WILL IMPROVE ON PRIOR SEX-STRATIFIED GENOME-WIDE ASSOCIATION STUDIES (GWAS) BY USING LARGER SAMPLE SIZES AND EXTENSIVELY HARMONIZED DATA. THIS INCLUDES A CROSS-COHORT PHENOTYPE HARMONIZATION AND POWERFUL MODELS USING AGE INFORMATION TO IMPROVE AD RISK ASSOCIATIONS. IN ADDITION, WE WILL, FOR THE FIRST TIME, EXPLORE THE ROLE OF RARE VARIANTS ON AD IN A SEX-SPECIFIC MANNER. AIM 2 WILL USE PARALLEL STRATEGIES TO AIM 1, BUT WILL FOCUS ON THE X CHROMOSOME, WHICH HAS REMAINED LARGELY UNEXPLORED IN THE FIELD OF AD GENETICS. FOR BOTH AIMS 1 AND 2, WE WILL FURTHER VALIDATE PUTATIVE ASSOCIATIONS B