# Biomarkers to track effective interventions that delay dementia onset in participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" trial

> **NIH NIH R56** · UNIVERSITY OF KENTUCKY · 2021 · $714,524

## Abstract

Project Summary
It is often hard to distinguish between Alzheimer’s disease (AD) and AD-related dementias (ADRD), including
Vascular contributions to Cognitive Impairment and Dementia (VCID), due to a similar clinical presentation of
memory loss and the presence of cardiovascular (CV) risk factors (e.g. hypertension, dyslipidemia). While CV
risk factors have available drug therapies, increased physical activity also significantly lowers these co-
morbidities. Unfortunately, evidence linking CV and exercise interventions to the prevention of cognitive decline
is inconclusive, nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions.
This ancillary R01 will use plasma-based biomarkers and neuroimaging from subjects enrolled in our NIH-
funded trial “Risk Reduction for Alzheimer’s Disease (rrAD; NCT02913664).” This phase II randomized
controlled trial will determine the independent and combined effects of Intensive pharmacological Reduction of
Vascular Risk factors (IRVR; i.e. blood pressure, lipids) and aerobic exercise (Ex) on cognitive function.
Participants were randomized into 2-year interventions (IRVR, Ex, IRVR+Ex, and a control arm of standard
care (SC)) with plasma and neuroimaging collected at baseline and yearly. Of the 513 rrAD subjects (63%
females; 34% aged 71-85; 13% African-American; 4% Hispanic/Latino), 41% of enrolled subjects have finished
their 2-year follow-up. The rrAD trial is anticipated to be completed by the end of October 2021 with an overall
attrition rate <15%. Banked longitudinal rrAD plasma samples will be used to test the hypothesis that 1)
benchmark AD, 2) benchmark VCID, and/or 3) novel circulating brain-derived biomarkers can be modulated by
positive lifestyle interventions. Aim 1 will test if the benchmark AD biomarkers Aβ42/Aβ40 ratio will increase,
while pTau181 will decrease, with IRVR+Ex. Higher ratios and lower tau will be associate with our secondary
outcome measure of preserved hippocampal volume measured by 3D T1-weighted MRI, as compared to SC.
Aim 2 will test if primary benchmark endothelial VCID biomarkers will reveal effects of vascular and exercise
interventions on cerebrovascular health. We will test if lower pathologic angiogenic proteins (i.e. VEGF-D,
PlGF, bFGF) measured longitudinally decrease with intervention. Lower expression will coincide with
secondary outcome measures of increased regional cerebral blood flow (i.e. arterial spin labeling, MRI) and
fewer white matter hyperintensities (i.e. T2 FLAIR, MRI). Aim 3 will test if vascular and exercise interventions
alter the neurotrophic cargo of circulating neuronal-enriched extracellular vesicles (EVs). We will test IRVR+Ex
lowers pro- (i.e. uncleaved) brain-derived neurotrophic factor (BDNF) and increases mature BDNF in neuronal-
enriched EVs. Higher BDNF will coincide with the secondary outcome measure of stronger resting-state
functional MRI connectivity associated with the default mode network. We hypoth...

## Key facts

- **NIH application ID:** 10459779
- **Project number:** 1R56AG074613-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** DWIGHT C. German
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $714,524
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459779

## Citation

> US National Institutes of Health, RePORTER application 10459779, Biomarkers to track effective interventions that delay dementia onset in participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" trial (1R56AG074613-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459779. Licensed CC0.

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