Clinical, imaging, and biomarker evidence of amyloid- and tau-related neurodegeneration in late-onset epilepsy of unknown etiology

Abstract

Accumulating evidence suggests amyloid and tau-related neurodegeneration may play a role in development of late-onset epilepsy of unknown etiology (LOEU). In this article, we review recent evidence that epilepsy may be an initial manifestation of an amyloidopathy or tauopathy that precedes development of Alzheimer's disease (AD). Patients with LOEU demonstrate an increased risk of cognitive decline, and patients with AD have increased prevalence of preceding epilepsy. Moreover, investigations of LOEU that use CSF biomarkers and imaging techniques have identified preclinical neurodegeneration with evidence of amyloid and tau deposition. Overall, findings to date suggest a relationship between acquired, non-lesional late-onset epilepsy and amyloid and tau-related neurodegeneration, which supports that preclinical or prodromal AD is a distinct etiology of late-onset epilepsy. We propose criteria for assessing elevated risk of developing dementia in patients with late-onset epilepsy utilizing clinical features, available imaging techniques, and biomarker measurements. Further research is needed to validate these criteria and assess optimal treatment strategies for patients with probable epileptic preclinical AD and epileptic prodromal AD.

Keywords: Alzheimer dementia; amyloid; epileptic preclinical Alzheimer disease; epileptic prodromal Alzheimer disease; late onset epilepsy; late onset epilepsy of unknown etiology; late-onset amyloid Beta-related epilepsy; tau.

Figure 1

Potential etiologies of late-onset epilepsy. If no etiology can be identified after comprehensive standard clinical evaluation including EEG, epilepsy-protocol MRI, and detailed clinical assessment, the presentation is consistent with late-onset epilepsy of unknown etiology (LOEU). Management of LOEU mirrors general management of epilepsy in older adults, with greater emphasis on monitoring for development of cognitive impairment and intervening on comorbid risk factors for cognitive decline.

Figure 2

Evaluation of late-onset epilepsy of unknown etiology (LOEU) and classification based upon results of biomarker testing and imaging. The AT(N) classification system for AD can be used to classify patients with late-onset epilepsy. “A” refers to amyloid biomarkers; “T” refers to tau biomarkers indicative of neurofibrillary tangles; “N” refers to evidence of neurodegeneration assessed by neuroimaging or biomarkers. PART, Primary Age-Related Tauopathy.