# Sporadic Alzheimer's Disease: A Bioenergetic Etiology?

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2022 · $370,195

## Abstract

PROJECT SUMMARY
This application aims to address the central question of whether brain bioenergetic dysfunction serves as an
etiologic mechanism underlying the initiation of late-onset sporadic Alzheimer's disease (sAD). Our
overarching hypotheses are that age, sex, and apolipoprotein E (APOE) genetic status—the most potent triad
of sAD risk factors—synergistically alter brain energy metabolism, and that bioenergetic changes trigger
alterations in amyloid homeostasis and synaptic transmission resulting in the onset of preclinical sAD. The
proposed studies will be carried out in three specific aims. Aims 1 and 2 will be performed in novel mouse
models that possess genetic conditions analogous to sAD (co-expression of human wild-type APP and human
APOE alleles: 2, 3, or 4), while Aim 3 will be conducted in blood samples collected from the aforementioned
sAD mouse models and a cohort of healthy, MCI, and early-stage sAD human subjects. Specifically, Aim 1 will
examine the combinatory role of age, sex, and APOE status on brain energy and amyloid metabolism to
directly assess the hypothesis that age-sex-APOE-mediated bioenergetic changes precede alterations in
amyloid homeostasis in the early aging brain. Aim 2 will address the hypothesis that synaptic vesicles function
and neurotransmission are significantly affected by alternations in brain bioenergetics. Aim 3 will assess the
hypothesis that alterations in brain bioenergetic and cognitive function can be predicted by bioenergetic
transcriptional changes in the blood. Our ultimate goals for this research are two-fold: (1) to define the
bioenergetic roles and specific processes involved in the development of sAD-risk phenotypes and (2) to
identify blood-based bioenergetic transcriptomic biomarkers that are predictive of brain changes in the
development of MCI and sAD. Achievement of these goals will advance our understanding of the complex
etiology of sAD. More importantly, the findings yielded from these investigations will provide valuable insight
into the identification of novel peripheral biomarkers that could potentially be used for early diagnosis of MCI
and sAD as well as mechanistic rationales that could guide the development of novel therapeutic strategies
that may be utilized for sAD prevention, risk reduction, and early intervention, particularly in the high-risk
population of women and APOE4 carriers.

## Key facts

- **NIH application ID:** 10359677
- **Project number:** 5R01AG061038-04
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Liqin Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,195
- **Award type:** 5
- **Project period:** 2019-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359677

## Citation

> US National Institutes of Health, RePORTER application 10359677, Sporadic Alzheimer's Disease: A Bioenergetic Etiology? (5R01AG061038-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359677. Licensed CC0.

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