Background

Acitretin is a retinoid drug used primarily to treat severe psoriasis. It can cause birth defects and other side effects typical of vitamin A overdose, including hair loss, elevated triglyceride levels, and drying of mucosal membranes, and therefore is used only in patients who do not respond to less-toxic psoriasis drugs. Acitretin acts as a retinoic acid receptor agonist. In preclinical models it increases expression of ADAM-10, the physiological α-secretase of the human amyloid precursor protein (APP). Acitretin was reported to boost non-amyloidogenic processing of APP in neuroblastoma cells and reduce Aβ levels in APP/PS-1 transgenic mice (see Tippman et al., 2009). It reportedly crosses the blood-brain barrier in mice (Holthoewer et al., 2012).

Findings

In 2010, a Phase 2 trial began at two sites, in Mainz and Rostock, Germany. It aimed to investigate efficacy and tolerability of a four-week course of 30 mg/day of acitretin capsules in 76 men and women with mild to moderate Alzheimer's disease. The primary outcome was differences in CSF APPSα levels, as measured at four weeks (see European Clinical Trials Database Trial Register). The trial ended in 2013 and was published in 2014. Twenty-one patients were randomized to acitretin (11) or placebo (10); none dropped out. The investigators reported a 25 percent intra-individual increase in CSF-APPsα in the treatment group between baseline and one month on aitrcetin, with statistical significance of 0.05 when controlled for older ages in the placebo than treatment group. APPs-β was reported to trend lower but was not statistically significant. CSF Aβ42, phospho-tau, and total tau remained unchanged. Side effects were as expected, with dryness of skin and mucous membranes, skin scaling, and hair loss. According to the authors, this pilot study provides proof of mechanism of increased ADAM-10 activity in response to acitretin in AD (Endres et al., 2014). 

Clinical Trial Timeline