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

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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 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.