Repurposing the NMDA Receptor Antagonist Memantine as a Cognitive Enhancer in Stage 0 Alzheimer's Disease in Persons with Down Syndrome - ABSTRACT Persons with Down syndrome (DS) develop the earliest documented form of Alzheimer's disease (AD)-type pathology. Approximately 50% of those with DS meet clinical dementia diagnosis criteria by 55 years of age, and it is estimated that persons with DS account for most cases of AD pathology overall in those younger than 50 years. According to the 2024 National Institute of Aging/Alzheimer’s Association revised criteria for diagnosis and staging of AD, all presymptomatic individuals with DS are now classified as having ‘Stage 0’ DS- associated AD (DSAD). Although some of the mechanisms underlying the development of DSAD might differ from those in the general population, it is also very likely that common mechanisms are present. Three years ago, we published the results of a randomized phase 2 trial of the AD drug memantine in which we investigated its safety and efficacy on cognitive and adaptive measures in adolescents and young adults with DS. In that study, we used standard doses of memantine and found no evidence of cognitive-enhancing effects in the primary analysis. Memantine was well tolerated, with infrequent mild-to-moderate side-effects observed. Surprisingly, however, when we measured plasma memantine levels in the study participants, we found that more than 90% of them had lower levels than those considered therapeutic in older patients with AD. This finding led us to perform an exploratory, post hoc analysis on cognitive data from the 23 study participants with near-or-above therapeutic blood levels as compared to 23 study matched participants in the placebo arm of the study. This analysis pointed to the possibility that doses of memantine larger than those approved for the treatment of patients with AD may be efficacious in enhancing episodic memory and short-term memory in persons with DS and that further studies were warranted. Here, we propose a project with two sequential aims (or phases) to test this hypothesis: Aim 1 (UG3 Phase). A single-site, open-label, phase 1b trial to investigate the safety, tolerability, pharmacokinetics (PK), and pilot assessment of the efficacy of higher-than-typical doses of memantine on enhancing cognition in adolescents and young adults with DS. Aim 2 (UH3 Phase): A two- site, randomized, double-blind, placebo-controlled phase 2a trial of the safety, efficacy, and tolerability of a therapeutically relevant dose of memantine on cognitive, adaptive, and quality-of-life outcome measures in adolescents and young adults with DS. Evidence of clinically relevant beneficial effects of memantine on the cognitive and/or adaptive abilities of those with DSAD Stage 0 would allow for a ‘naturalistic’ neuroprotective trial in this population as this medication starts to be prescribed routinely for those with DS who are not yet affected by AD neuropathology. Findings of this study could also lead to the investigation of higher-than- standard doses of memantine in some patients with AD, particularly in younger, otherwise healthy patients with early-onset dementia, and, therefore, may even produce valuable information toward more effective treatment strategies for those with familial and sporadic AD in the general population.
