Case Report: Longitudinal evaluation of cerebrospinal fluid Alzheimer’s disease core biomarkers in a case of refractory late-onset epilepsy of unknown etiology

Abstract

In recent years, late-onset epilepsy of unknown etiology (LOEU) has increasingly been recognized as a risk factor for Alzheimer’s disease (AD) and other forms of dementia. We present a case of refractory LOEU with progressive cognitive decline, longitudinally evaluated over more than 20 years using neuropsychological tests, cerebrospinal fluid (CSF) AD core biomarkers (Aβ42/40 ratio, p-tau), electroencephalography, and neuroimaging. The CSF AD core biomarkers were consistently positive, indicating the presence of both amyloid and tau pathology; however, CSF Aβ levels markedly decreased in parallel with improved seizure control. Notably, the addition of low-dose perampanel (1 mg/day) led to improvement in both cognitive function and seizure control, while 18F-flutemetamol positron emission tomography remained visually negative despite exceeding the predefined quantitative Centiloid threshold. Two years later, seizure frequency increased again, cognitive function deteriorated, and amyloid PET became visually positive, accompanied by an increase in the quantitative Centiloid value. This longitudinal observation suggests that chronic epileptic activity may modify or confound the interpretation of CSF AD biomarker profiles and contribute to cognitive decline, while concomitant early or slowly progressive AD pathology cannot be excluded. The overall biomarker trajectory, including persistently positive CSF AD biomarkers and progressive amyloid PET findings, is compatible with evolving AD pathology, although the marked decline in absolute CSF Aβ concentrations during improved seizure control suggests that chronic epileptic activity may also influence biomarker dynamics. Careful interpretation of AD biomarkers is therefore essential in patients with LOEU, particularly in the era of anti-amyloid therapies.