# Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $1,130,295

## Abstract

PROJECT SUMMARY / ABSTRACT
 The mission for the Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal
Endophenotype project is to determine the complex interaction between chromosomal sex and the major risk
factors for late onset Alzheimer’s (LOAD): age, APOE*4 genotype and maternal history of AD. As LOAD accounts
for the greatest incidence and prevalence of the disease, determining molecular mechanisms relevant to LOAD
has the potential for greatest impact. Further, targeting early stage transitions of risk have the greatest potential
for therapeutic efficacy. Thus, research proposed herein focuses on the prodromal / preclinical stage of LOAD
and the sex differences that underlie early risks of LOAD progression. Elucidation of sex differences in the
mechanisms driving prodromal LOAD will lead to identification of therapeutic targets to change the trajectory of
the disease to prevent, delay and potentially reverse course of developing LOAD.
 To achieve this goal, we have assembled an integrative research team with expertise spanning sex
differences in: human brain imaging endophenotypes that emerge during pre-clinical / prodromal phase of LOAD,
molecular mechanisms of complex interactions across sex, age, ApoE and mitochondrial bioenergetics and
innovative translational AD animal model development, data science and computational systems biology
bioinformatics to identify sex specific endophenotypes and therapeutic targets for precision health,
 Our proposed program of research is organized and integrated across three specific aims designed to
determine the complex mechanisms and pathways underlying sex differences in the prodromal LOAD
endophenotype. Translationally, we have anchored our approach in the complex biology of humans and
integrated that complexity into an innovative animal model that combine LOAD risk factors of age, sex, APOE*4
genotype and maternal mitochondrial DNA inheritance. Aim 1 will establish sex differences in brain prodromal
endophenotype using brain PET and MRI imaging in parallel with innovative 31P-MRS imaging of mitochondrial
function in human brain. Aim 2 is designed to mechanistically determine the systems biology pathways and
networks that emerge during the prodromal phase of LOAD. With UI-JAX Model-AD, we will develop a novel and
translationally valid model of LOAD that addresses each of the 4 LOAD risk factors including maternal inheritance
of AD through inheritance of the maternal mitochondrial genome and bioenergetic capacity (LOADm4: aged
mtDNA-hAPP-hAPOEe4). In Aim 3, multi-scale data from Aims 1 and 2 will be analyzed using an innovative and
sensitive computational systems biology approach to detect sex differences in the prodromal transition state of
LOAD risk and therapeutic targets to mitigate risk.
 Outcomes of our analyses will elucidate molecular mechanisms that emerge in midlife and that increase risk
of developing AD later in life. Collectively, these data will provide th...

## Key facts

- **NIH application ID:** 10470744
- **Project number:** 5R01AG057931-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** ROBERTA EILEEN BRINTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,130,295
- **Award type:** 5
- **Project period:** 2018-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470744

## Citation

> US National Institutes of Health, RePORTER application 10470744, Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype (5R01AG057931-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470744. Licensed CC0.

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