Evaluating the Efficacy of Levetiracetam on Non-Cognitive Symptoms and Pathology in a Tau Mouse Model

Background/Objectives: Alzheimer's disease (AD) is marked by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs), leading to cognitive decline and debilitating non-cognitive symptoms. This study aimed to evaluate compounds from four different classes in a short-term (7-day) study using transgenic tau mice to assess their ability to reduce non-cognitive symptoms. The best candidate was then evaluated for longer exposure to assess non-cognitive symptoms, cognition, and pathology. Methods: Tg4510 mice, expressing mutated human tau (P301L), were administered with levetiracetam, methylphenidate, diazepam, and quetiapine for 7 days at 6 months old, when pathology and cognitive deficits are established. Drugs were given in the diet, and non-cognitive symptoms were evaluated using metabolic cages. Levetiracetam was chosen for longer exposure (3 months) in 3-month-old Tg4510 mice and non-transgenic controls to assess behavior and pathology. Results: After 3 months of diet, levetiracetam mildly reduced tau pathology in the hippocampus but did not improve cognition in Tg4510 mice. Interestingly, it influenced appetite, body weight, anxiety-like behavior, and contextual fear memory in non-transgenic animals but not in Tg4510 mice. Conclusions: While levetiracetam has shown benefits in amyloid deposition models, it had limited effects on tau pathology and behavior in an animal model of tau deposition, which is crucial for AD context. The differential effects on non-transgenic versus Tg4510 mice warrant further investigation.