Cognitive and Biomarker Signatures of Late-Onset Temporal Lobe Epilepsy: Toward Non-Alzheimer Neurodegenerative Mechanisms.

BACKGROUND AND

OBJECTIVES

Late-onset unexplained epilepsy (LOUE) represents a substantial proportion of epilepsies with onset after 50 years and often manifests as temporal lobe epilepsy (LO-TLE). Although a link with Alzheimer disease (AD) has been suggested, only a subset of LO-TLE shows AD-related biomarkers, indicating biological heterogeneity. This study aims to characterize the cognitive and CSF phenotype of LO-TLE and compare it with healthy controls (HCs) and patients with mild cognitive impairment due to AD (MCI-AD).

METHODS

This Italian cross-sectional cohort study included LO-TLE patients with normal CSF β-amyloid (Aβ) biomarkers, MCI-AD, and age-matched and sex-matched HC. Participants underwent structural MRI, neuropsychological assessment, and CSF biomarkers assay, including neurofilament light chain (NfL) and the phosphorylated-to-total tau ratio (p/t-tau). Cortical thickness and subcortical volumes were quantified from structural MRI. Cognitive performance was summarized using principal component analyses. Group differences in imaging, cognition, and CSF biomarkers were assessed, and associations between CSF markers and cognition were examined within groups.

RESULTS

The study included 18 LO-TLE, 24 MCI-AD, and 17 HC. LO-TLE showed preserved cortical thickness and subcortical volumes comparable with HC, whereas MCI-AD exhibited widespread cortical thinning and medial temporal atrophy. Despite normal imaging, LO-TLE showed lower performance compared with HC in episodic memory (t(53) = -7.79, pFDR < 0.001), short-term memory (t(53) = -2.94, pFDR = 0.007), language (t(53) = 4.12, pFDR < 0.001), and executive functions (t(53) = -3.76, pFDR < 0.001), while attention was preserved. Global cognitive performance further distinguished LO-TLE from MCI-AD, with the former group performing better (t(53) = 4.21, pFDR < 0.001). LO-TLE CSF profiles were characterized by low NfL levels and a p/t-tau ratio below the proposed cutoff of 0.17, whereas MCI-AD showed pathologic Aβ and tau alterations, elevated NfL, and p/t-tau ratio above 0.17. In LO-TLE, a higher p/t-tau ratio was associated with better performance on global cognition (rs = 0.585, pFDR = 0.032) and short-term memory (rs = 0.588, pFDR = 0.032), whereas no associations emerged in MCI-AD.

DISCUSSION: LO-TLE with normal CSF AD biomarkers is characterized by distinct cognitive and biological features compared with MCI-AD, suggesting a disease process independent of AD. The low p/t-tau ratio may reflect alternative pathophysiologic mechanisms and warrants further investigation in larger longitudinal studies to clarify the underlying pathology and clinical trajectories.