Biomarkers to Track Effective Interventions that Delay Dementia Onset in Participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" Trial

Alzheimer’s disease (AD) and AD-related dementias (ADRD), including Vascular contributions to Cognitive Impairment and Dementia (VCID), present with similar cardiovascular (CV) risk factors (e.g. hypertension, dyslipidemia) contributing to memory loss that could be reduced through effective lifestyle interventions (e.g. pharmacotherapies, exercise). 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).” 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 in 513 cognitively normal older adults (65-79 y) with family history of AD and who have hypertension/dyslipidemia. Participants were randomized into two-year interventions (IRVR, Ex, IRVR+Ex, and a control arm of standard care) with plasma and neuroimaging collected at baseline and yearly. Longitudinal rrAD samples will be used to test the hypothesis that 1) benchmark AD, 2) benchmark VCID, or 3) novel circulating brain-derived biomarkers can be modulated by positive lifestyle interventions. Aim 1 will test if the benchmark AD biomarker (plasma Aβ42/Aβ40 ratios) will increase with IRVR+Ex and correlate to hippocampal volume. Aim 2 will test if the MarkVCID endothelial signaling kit (i.e. VEGF-D, PlGF, and bFGF) developed as a benchmark VCID biomarker will decrease with IRVR+Ex concomitant with improved cerebral blood flow and fewer white mater hyperintensities. Aim 3 will test if IRVR+Ex alters circulating brain-enriched biomarkers (neuronal-enriched extracellular vesicles (EVs) and endothelial EVs). Higher BDNF in neuronal- enriched EVs and lower VEGF-D in endothelial EVs will coincide with stronger resting-state functional MRI connectivity associated with the default mode network. This grant will identify biomarkers that track effective lifestyle interventions to delay dementia in high-risk individuals with CV risks prior to cognitive decline.