# Mechanisms and Predictors of Brain Aging in Healthy Aging, Preclinical AD and MCI

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2022 · $666,046

## Abstract

The distinction between healthy aging and pathology is imprecise and is clouded by overlap
among normal brain aging markers and neural changes associated with Alzheimer’s disease
(AD). Even in the case of beta-amyloid deposition, a key hallmark of AD, 20-30% of healthy
older individuals show elevated amyloid, yet it remains unclear if these individuals will
necessarily progress to dementia. Therefore, there is significant need for studies designed to
investigate novel, lesser-studied mechanisms of brain aging, which may help disambiguate the
neural changes that are early indicators of a pathological trajectory vs. signs of normal aging.
The present study aims to provide new insight into neurocognitive aging with a multimodal
investigation of important and understudied mechanisms of brain aging from molecular changes
(iron accumulation and Aβ deposition) to synaptic changes (neurite complexity) to changes in
brain function (BOLD modulation of activation) and their influence on cognition in middle-aged,
older and MCI individuals. Critically, we propose to prospectively study healthy aging individuals
who systematically vary in risk for AD (cognitively healthy low risk for AD, cognitively healthy
elevated risk for AD) alongside individuals with Mild Cognitive Impairment (MCI), who are more
likely to be in the early stages of neuropathological development. Through this approach, we
aim to help elucidate some of the mechanisms underlying key aspects of brain and cognitive
aging in healthy adults and also to distinguish which age-related brain changes may signal
preclinical AD vs. non-pathological aging. The first aim proposes to examine brain iron
accumulation as an early marker for cognitive and neural decline. We will study the impact of
increased brain iron on cognitive performance and fMRI measured brain activation in healthy
aging, preclinical AD and MCI. Secondly, we aim to examine the effect of synaptic complexity
on cognitive performance and brain activation across risk groups. We will examine the
relationship of both iron accumulation and synaptic complexity measures to beta-amyloid
accumulation in preclinical aging and MCI to gauge whether these variables may serve as
sensitive biomarkers for pathological aging. Finally, we plan to test the hypothesis that
differences in neural modulation to cognitive difficulty as measured with fMRI may serve as a
biomarker for preclinical AD. Completion of the current study is expected to advance
understanding of the mechanisms and predictors of healthy brain aging versus a pathological
aging trajectory.

## Key facts

- **NIH application ID:** 10404663
- **Project number:** 5R01AG057537-05
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Karen M Rodrigue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $666,046
- **Award type:** 5
- **Project period:** 2018-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404663

## Citation

> US National Institutes of Health, RePORTER application 10404663, Mechanisms and Predictors of Brain Aging in Healthy Aging, Preclinical AD and MCI (5R01AG057537-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404663. Licensed CC0.

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