Cognitive signatures of Late-Onset Temporal Lobe Epilepsy: toward for non–Alzheimer neurodegenerative mechanisms

Late-onset epilepsy (LOE) is the third most common neurological disorder in older adults, following stroke and dementia. This condition is particularly relevant in countries such as Italy, where the mean population age ranks among the highest worldwide. In older adults, the leading causes of epilepsy are mainly cerebrovascular disease and brain tumors; however, a considerable proportion of cases, ranging from 33% to 53%, occur without an identifiable etiology and are classified as Late-Onset Epilepsy of Unknown Etiology (LOEU). Temporal lobe epilepsy (TLE) is the most common clinical phenotype within LOUE (LO-TLE). Growing evidence suggests an association between LO-TLE and neurodegenerative diseases, particularly Alzheimer’s disease (AD). The present study builds upon the work of Ballerini et al. (2025), which showed that patients with late-onset temporal lobe epilepsy (LO-TLE) of short disease duration and in the absence of Alzheimer’s disease–related biomarkers, exhibited cortical and subcortical morphometric patterns comparable to those of healthy controls (HC), yet clearly distinct from mild cognitive impairment (MCI) groups, including MCI due to Alzheimer’s disease (MCI-AD). Expanding on these findings, we assessed the cognitive performance of 24 patients with MCI-AD and 18 LO-TLE patients derived from the Ballerini et al. (2025) cohort and compared them with 17 newly recruited HC. Our results showed that LO-TLE patients performed significantly worse than controls in language, memory, and executive functions, indicating a dissociation between preserved structural integrity and impaired cognitive performance. Nevertheless, their cognitive profile remained distinct from that of MCI-AD patients, who showed greater deficits across nearly all cognitive domains. These findings challenge the prevailing assumption that LO-TLE and MCI-AD share overlapping cognitive characteristics, instead supporting the existence of distinct neuropsychological profiles and potentially divergent underlying mechanisms. Another clinically relevant observation emerging from this study is that, despite growing evidence of cognitive deficits across multiple domains in LO-TLE, these impairments are often attributed solely to epilepsy. Consequently, such patients rarely receive the cognitive interventions commonly provided to individuals with MCI in the absence of epilepsy. Finally, LO-TLE patients did not constitute a homogeneous group. To gain deeper insight into interindividual variability and disease progression, several clinical cases of patients for whom longitudinal follow-up data were available, were analysed and discussed in detail.