The proposed proof-of-concept study will use an 18-month randomized, placebo-controlled, double-blind, parallel-group clinical trial design to investigate the effects of IPE (available as Vascepa® in the United States) on rCBF, CSF AD biomarkers, and cognition in 150 cognitively-healthy Veterans ages 50-70 years at increased risk for AD due to their combined independent risk factors of parental history of AD, increased APOE4 prevalence, and Veteran-related risk factors including high vascular risk profiles, TBI, and PTSD. The primary aim of the trial (Specific Aim 1) is to assess whether IPE increases 18-month rCBF in a statistically-defined region of interest (sROI) in a population of middle-aged veterans with parental history of AD compared to placebo. Key secondary aims within this proof-of-concept pilot RCT are: (Specific Aim 2) to assess whether IPE decreases CSF A?42; and (Specific Aim 3) to assess whether IPE improves cognitive performance on the ADCS-PACC battery compared to placebo. Data collected within this clinical trial will also allow exploratory analyses of the effects of IPE on measures of axonal and neuronal health, including CSF biomarkers (total tau, phosphorylated tau [p-tau], neurofilament light [NFL] protein, soluble amyloid precursor protein ? and ? [sAPP-? and sAPP-?], monocyte chemotactic protein 1 [MCP1], YKL-40, and other CSF measures) and neuroimaging biomarkers (diffusion tensor imaging, volumetric changes, 4D flow measures, and white matter hyperintensity measures among others). In addition, data collection from this trial will allow for exploration of the impact of previous TBI and/or PTSD on response to therapy. We hypothesize that in this population, IPE will beneficially affect mechanisms central to AD pathology by: 1) increasing rCBF within the sROI; 2) reducing CSF A?42; and that these neurobiological changes will be associated with 3) an increased ADCS-PACC cognitive composite score. While recognizing that the proposed trial is not addressing all potential effects of IPE, such as changes in measures of inflammation or oxidative stress, we will store neuroimages and blood and CSF samples for future analyses of other potential mechanisms.
January 2017 to January 2022
This project led by: Cynthia Carlsson, MD