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Description
Project Summary
It is often hard to distinguish between Alzheimer’s disease (AD) and AD-related dementias (ADRDs), 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 initial rrAD subjects
(63% females; 34% aged 71-85; 13% African-American; 4% LatinX), 89% (458 subjects) have longitudinal
serum and neuroimaging biomarkers available for linear mixed-models analyses. 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 and pTAu 231 will decrease, the
greatest with IRVR+Ex. Higher ratios and lower tau will be associated with our secondary outcome measures
of preserved hippocampal volume (T1-weighted MRI) and preserved default-mode network (DMN) connectivity
measured by resting-state functional (rs-f)MRI. Aim 2 will test if primary benchmark VCID biomarkers will
reveal effects of vascular and exercise interventions on cerebrovascular health. We will test if lower pathologic
pro-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 of
stronger DMN rs-fMRI connectivity. We hypothesize that AD, VCID, and EV biomarkers not only identify
individuals with high risk for AD/ADRDs but can also track efficacy of independent and combined lifestyle
interventions that improve cerebrovascular health and delay dementia onset in sedentary adults.
Status | Active |
---|---|
Effective start/end date | 9/1/23 → 8/31/26 |
Funding
- National Institute on Aging: $2,600,455.00
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Projects
- 1 Active
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Diversity Supplement for Jenny Lutshumba
Stowe, A. (PI) & Lutshumba, J. (CoI)
9/1/23 → 8/31/26
Project: Research project