Downregulating Functional Hyperactivity in APOE Ε4 Carriers: an Important Avenue for Early‐life Risk Reduction

Background Hyperactivity in the brain regions supporting episodic memory (the hippocampus and default mode network) drives the accumulation of Alzheimer’s Disease (AD) neuropathology and the resulting cascade of brain network disruption. Pharmacologically reducing hippocampal hyperactivity using the anti‐seizure medication Levetiracetam improves memory in individuals with prodromal AD. Carriers of an APOE e4 genetic risk variant show patterns of brain hyperactivity from youth. This study tests if Levetiracetam can prophylactically manage hippocampal hyperactivity in mid‐age APOE e4 carriers, and if such a reduction is associated with improved cognitive performance. Method Fifty cognitively healthy adults (aged 45‐65 years), differentiated by APOE genotype (25 e4 carriers, 25 e33 carriers), are participating in a double‐blind, placebo‐controlled trial of Levetiracetam (125mg bidaily for two‐weeks). Analyses will primarily focus on change in task‐related and resting functional magnetic resonance imaging (fMRI) brain blood‐oxygen‐level‐dependent response (BOLD) following Levetiracetam. In addition, the everyday cognitive effects of this manipulation will be evaluated, including on daily smartphone‐based measures of memory and attention. Result To date, 43 participants are enrolled in the 8‐week intervention (23 of whom have completed). Adverse events relating to the study drug have been minimal; only one participant has withdrawn in response to experiencing side‐effects. APOE genotype and treatment order (Levetiracetam, placebo) will be unblinded at the end of data collection (anticipated April 2023). Conclusion Conclusions from this work will help expose routes to AD risk reduction, and the potential for repurposing an existing treatment for mid‐age individuals at elevated genetic risk for future dementia. This research will motivate longer‐term clinical trials for risk reduction strategies across the lifespan.