Heterogeneous responses to memantine in Alzheimer's disease: A precision medicine approach using iPSC models

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive and functional decline. Memantine, a commonly prescribed N-methyl-D-aspartate receptor antagonist, appears to slightly delay symptom progression in moderate or advanced stages of AD. Clinical response is highly variable across patients with some benefiting but others not. Induced pluripotent stem cell (iPSC)-derived neurons can provide a donor-dependent model to predict the therapeutic efficacy of memantine.

We generated iPSC-derived cortical neurons from 19 individuals (12 AD and 7 cognitively unimpaired [CU]). Assays for calcium influx and oxidative stress were developed and optimized for neurons. Memantine was tested under different treatment conditions. Neurons were exposed to glutamate/glycine to induce calcium influx and menadione to generate oxidative stress. Memantine treatment was applied either acutely (1 hour) or as a 24-hour pre-treatment to evaluate its neuroprotective effects.

Peripheral blood mononuclear cell-derived iPSCs were successfully differentiated into functional neurons, exhibiting comparable electrophysiological properties between AD and CU lines. Calcium influx assays revealed a heterogeneous response among AD and CU neurons, with AD neurons generally displaying higher baseline fluorescence. Memantine treatment for 24 hours significantly reduced calcium influx, with a -9.85% average reduction and a range of -0.39% to -39%. Similarly, reactive oxygen species assays showed menadione-induced oxidative stress was attenuated by 24-hour memantine pre-treatment for a mean -26.05% reduction and a range of -4.23% to -72.21%. The observed variability indicates differential susceptibility to excitotoxicity reduction and or oxidative stress mitigation across lines.

This exploratory study establishes a robust in vitro platform to test memantine efficacy using iPSC-derived neurons to model calcium dysregulation and oxidative stress in AD. The observed variability in response highlights the importance of personalized approaches in AD treatment, emphasizing the potential for iPSC-based platforms in precision medicine.