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https://www.alzforum.org/news/conference-coverage/going-indirect-can-therapies-halt-alzheimers-outside-brain

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21 Dec 2019

For therapies taking aim at Alzheimer’s disease, exerting an effect in the brain seems critical. And obvious. But according to results on display at 12th Clinical Trials on Alzheimer’s Disease conference, held December 4–7 in San Diego, California, a therapy might also influence the brain without ever entering it. Researchers reported that apabetalone, a drug that tweaks expression of hundreds of genes via an epigenetic mechanism, reduced inflammatory proteins in the blood, including those that make inflammation-stoking leukocytes cling to blood vessel walls. Apabetalone appeared to slow cognitive decline, but only among those who were most impaired at baseline. Separately, a fresh statistical analysis of AMBAR—a trial that evaluated a plasma-exchange protocol—claimed a cognitive benefit in people with moderate AD, and hinted it could work in people with milder disease. Both trials were plagued by the limitation that they did not use biomarkers to select people who truly had AD, muddling signs of efficacy.

Apabetalone exerts its sway by inhibiting Bromodomain Extraterminal Domain (BET) proteins, which bind to the acetylated lysines that mark open, active stretches of chromatin. BET proteins then recruit transcription factors to the scene to switch on gene expression. Apabetalone essentially blocks the association between BET and acetylated lysines, squelching transcription of hundreds of genes. Previously, researchers reported that BET proteins drove the expression of myriad genes involved in inflammation, lipid metabolism, and vascular function, casting apabetalone as a candidate treatment for cardiovascular and other chronic diseases of aging.

At the AD/PD meeting in Lisbon earlier this year, Ewelina Kulikowski of Resverlogix, the Calgary-based company developing the drug, reported that in cell culture, apabetalone blocked expression of pro-inflammatory cytokines and leukocyte adhesion molecules on vascular endothelial cells; this kept monocytes from latching onto them (May 2019 conference news). Apabetalone also spared LPS-ravaged mice from damaging neuroinflammation.

At CTAD, Kulikowski presented data suggesting the drug douses vascular inflammation in people, too. She measured more than 1,300 proteins within plasma samples collected from 94 participants in the ASSURE trial, which evaluated a 26-week course of 200 mg of apabetalone for its effect on atherosclerotic plaques in people with cardiovascular disease (Nicholls et al., 2016). Kulikowski found that between baseline and 26 weeks, samples from the apabetalone group had significant drops in inflammatory mediators, particularly chemokines and cell adhesion receptors known to snag circulating leukocytes and rev up vascular inflammation.

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