Francesco Bruno ¹ Patrizia Spadafora ^1* Ida Veltri ² Mario Luca Cuconati ³ Annamaria Cerantonio ¹ Selene De Benedittis ⁴ Beatrice Maria Greco ¹ Gemma Di Palma ¹ Olivier Gallo ¹ Luigi Citrigno ¹ Antonio Qualtieri ¹ Maurizio Cundari ⁵ FRANCESCA CAVALCANTI ^1*

• ¹ Institute for Biomedical Research and Innovation (IRIB), Italian National Research Council (CNR), MANGONE (CS), Italy
• ² ASST Lodi, Lodi, Italy
• ³ School of Medicine and Surgery, University Magna Graecia of Catanzaro, Catanzaro, Calabria, Italy
• ⁴ Institute of Neurological Sciences, National Research Council (CNR), Mangone, Italy
• ⁵ Lund University, Lund, Skane County, Sweden

Introduction. Temporal lobe epilepsy is the most common form of focal epilepsy, often associated with cognitive impairments, particularly in memory functions, and depression. Sex and APOE ε4 genotype play a crucial role in modulating cognitive outcomes and depression in various neurological conditions like Alzheimer's disease. However, the combined effects of APOE genotype and sex on cognitive performance and depression in temporal lobe epilepsy have not been previously investigated.Objective. This study aims to i) identify impaired cognitive performance and clinically relevant depression; ii) explore the interaction between sex and APOE ε4 genotype on cognitive performance and depression in individuals with temporal lobe epilepsy. Methods: We used a comprehensive battery of neuropsychological tests to assess domains such as learning and memory, attention, executive functioning, language, and visuospatial constructional skills and the Hamilton Depression Rating Scale. We also performed APOE genotyping to assess its role in the study. The final sample was composed by fifty-four patients (53.7% female). Cognitive performance and depression were analyzed using normative cut-off scores. To examine the main effects and interactions of sex and APOE ε4 carrier status on neuropsychological test scores and the Hamilton Depression Rating Scale, we also conducted a two-way ANOVA. Results. Female APOE ε4 carriers compared to normative cut-offs, exhibited poor performance on multiple test scores, including MMSE, Rey Auditory Verbal Learning Test, Corsi Block-Tapping Task, Verbal Fluency Test, Raven's Standard Progressive Matrices and Pentagon-copying Test. Males showed impairment only in visuo-spatial short-term memory. ANOVA analysis revealed significant main effects of APOE ε4 status and sex on MMSE, Rey Auditory Verbal Learning Test, Verbal Fluency, Raven's Standard Progressive Matrices and Pentagon-copying Test scores. Specifically, female APOE ε4 carriers performed consistently worse than other groups on many tasks. For depression, only an effect of sex emerged. Females scored higher besides APOE genotype. Conclusions. These findings underscore the importance of considering both sex and APOE genotype when assessing cognitive performance in patients with temporal lobe epilepsy. This has potential implications for personalized therapeutic strategies, emphasizing the need for targeted assessment and intervention.