Does Alzheimer's disease with mesial temporal lobe epilepsy represent a distinct disease subtype?

Abstract

Alzheimer's disease (AD) patients have a high risk of developing mesial temporal lobe epilepsy (MTLE) and subclinical epileptiform activity. MTLE in AD worsens outcomes. Therefore, we need to understand the overlap between these disease processes. We hypothesize that AD with MTLE represents a distinct subtype of AD, with the interplay between tau and epileptiform activity at its core. We discuss shared pathological features including histopathology, an initial mesial temporal lobe (MTL) hyperexcitability followed by MTL dysfunction and involvement of same networks in memory (AD) and seizures (MTLE). We provide evidence that tau accumulation linearly increases neuronal hyperexcitability, neuronal hyper‐excitability increases tau secretion, tau can provoke seizures, and tau reduction protects against seizures. We speculate that AD genetic mutations increase tau, which causes proportionate neuronal loss and/or hyperexcitability, leading to seizures. We discuss that tau burden in MTLE predicts cognitive deficits among (1) AD and (2) MTLE without AD. Finally, we explore the possibility that anti‐seizure medications improve cognition by reducing neuronal hyper‐excitability, which reduces seizures and tau accumulation and spread. Highlights We hypothesize that patients with Alzheimer's disease (AD) and mesial temporal lobe epilepsy (MTLE) represents a distinct subtype of AD. AD and MTLE share histopathological features and involve overlapping neuronal and cortical networks. Hyper‐phosphorylated tau (pTau) increases neuronal excitability and provoke seizures, neuronal excitability increases pTau, and pTau reduction reduces neuronal excitability and protects against seizures. The pTau burden in MTL predicts cognitive deficits among (1) AD and (2) MTLE without AD. We speculate that anti‐seizure medications improve cognition by reducing neuronal excitability, which reduces seizures and pTau.

The Interplay Between Epilepsy and Alzheimer’s Disease: A Pas De Deux

“…Alzheimer's disease is associated with an 8-10-fold higher risk of developing focal epilepsy than the general population. 3 Up to 42% of AD without epilepsy show evidence of subclinical focal seizures and interictal epileptiform discharges (IEDs) on EEG. 1,3 It has been postulated that hippocampal dysfunction and hyperexcitability in AD ultimately give rise to mesial temporal lobe epilepsy (MTLE).…”

“…3 Up to 42% of AD without epilepsy show evidence of subclinical focal seizures and interictal epileptiform discharges (IEDs) on EEG. 1,3 It has been postulated that hippocampal dysfunction and hyperexcitability in AD ultimately give rise to mesial temporal lobe epilepsy (MTLE). 1,3 The authors add to the existing body of evidence by finding a causal link between genetic predisposition to AD and an increased risk of focal epilepsy with hippocampal sclerosis (HS) validated by replication analysis.…”

“…1,3 It has been postulated that hippocampal dysfunction and hyperexcitability in AD ultimately give rise to mesial temporal lobe epilepsy (MTLE). 1,3 The authors add to the existing body of evidence by finding a causal link between genetic predisposition to AD and an increased risk of focal epilepsy with hippocampal sclerosis (HS) validated by replication analysis. Does that imply all AD with HS have focal epilepsy, or should they be treated?…”

“…However, their analysis did not account for the APOEe4 allele, which has a robust association with amyloid burden and is also an important risk factor for LOE. 3 Therefore, subsequent MR studies should focus on examining the interaction between APOEe4, amyloid biomarkers, and epilepsy.…”

The multifactorial etiology of cognitive deficits in epilepsy and the neuropathology of mesial temporal lobe epilepsy beyond hyperphosphorylated tau

“…The multifactorial etiology of cognitive deficits in epilepsy and the neuropathology of mesial temporal lobe epilepsy beyond hyperphosphorylated tau Dear Editor, With great interest, we followed the recent review by Zawar and Kapur 1 on the overlap between mesial temporal lobe epilepsy (MTLE) and Alzheimer's disease (AD). The authors propose (1) that MTLE and AD share histopathological features and they claim (2) that hyperphosphorylated tau (p-tau) burden is the predominant predictor of cognitive deficits in MTLE with and without AD.…”