Treatment of Alzheimer disease in Down syndrome

Down syndrome (DS) is the most common genetically driven intellectual disability. Neuro pathological evidence of an associa‐ tion between Alzheimer disease (AD) and DS was published 11 years before trisomy 21 was described as the cause of DS.1 AD‐type pathology is almost universal in patients with DS in their 40s, although the develop ment of clinically detectable cognitive decline typically lags behind the pathology by 20–25 years.2 As life expectancy of patients with DS approaches 60 years in developed countries, the comorbidity of DS and AD is becoming an increasingly important clini‐ cal issue.1,2 Clinical trials of approved AD therapies for patients with DS are, there‐ fore, welcome. Previous work included pio‐ neering case series and one inconclusive randomized placebo‐ controlled trial of the an ticholinesterase drug donepezil.3 A recent study by Hanney et al.,4 named Meman tine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS; NCT00240760 at clinical‐ trials.gov), is an important addition to the field. This study was a randomized, double‐ blind, placebo‐controlled trial to assess safety and efficacy of memantine, an N‐methyl‐d‐ aspartate (NMDA) receptor antagonist that is approved for the treatment of cog‐ nitive decline in AD, in indivi duals with DS. Although 1‐year‐long treatment with meman tine was well‐ tolerated in this patient population, efficacy data were disappointing. The MEADOWS trial was well‐ conducted and is a commendable achievement, given the difficulties of recruiting and assur‐ ing protocol compliance in patients with DS. The trial design was based on previous findings by members of the same research team that people with DS over the age of 40 years without clinically detectable demen‐ tia experienced, on average, an 11% decline in neuropsychological measures of atten‐ tion, executive function and memory over the course of 1 year.5 The study involved 173 patients with DS, 88 of whom were randomly assigned to memantine and 85 of whom were randomly assigned to placebo.4 The primary end points were change in cognition and function, as measured on the DS atten‐ tion, memory and executive function scales (DAMES) score and the adaptive behaviour scale (ABS) parts I and II. After 1 year of treatment, no differences in these measures were observed between the memantine and control groups.