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 (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). 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 preserved default-mode network (DMN) connectivity measured by resting-state functional (rs-f)MRI. 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.