Epilepsy and AD: New Findings

It has long been known that the incidence of epilepsy in the setting of AD (Alzheimer's disease) is elevated. It is also clear that antiepileptic drug (AED) treatment is often less than optimal in these patients. The reasons have been unclear, and the mechanisms of the epilepsy are not well characterized. This has created somewhat of a clinical conundrum, as epilepsy can worsen both the cognitive and behavioral manifestations of AD. So, while I don't anticipate using this space to discuss basic science often, I think the paper by Palop and Mucke is of note.

This article is largely a discussion of beta amyloid proteins (AB) and amyloid precursor protein (APP). The focus is on attempting to ascertain exactly how these proteins disrupt brain function, by looking at human APP (hAPP), as well as Tau proteins, in mouse models. The authors note that transgenic mice expressing hAPP show seizure activity even prior to clinical manifestations of AD-like activity, and in the absence of frank neuronal loss. Thus, it's not only neuronal damage per se that causes epilepsy in these patients: Direct effects of abnormal proteins also are a factor, perhaps largely neuronal network disruptions from elevated AB levels. So, it is the interactions between groups of neurons, rather than the function of individual neurons, which may be the primary abnormality in this setting. Network effects are also of great significance in epilepsy. Importantly, interventions which prevented seizures also prevented th e appearance of cognitive deficits, reinforcing the mechanistic linkage between the two.

Additional evidence considered include:

Differential epilepsy incidence

The authors consider epilepsy incidence in different kinds of AD: There is an increase in epilepsy incidence in patients with sporadic AD which appears independent of disease stage. The incidence is much higher in patients with early onset disease (with a relative risk of up to 87!). Inherited forms of AD which affect human APP show an even higher epilepsy incidence, as do persons with Down's syndrome, who have an extra hAPP gene copy.

Epileptiform abnormalities without dementia

Inheritance of apolipoprotein E4, the best defined genetic risk factor for AD, may be associated with subclinical epileptiform EEG activity in carriers without dementia. Similar EEG findings are seen in relatives of persons with early onset AD. Also, Apo E4 is associated with cognitive impairment in people with intractable epilepsy. Thus, Apo E4 may be associated with abnormal neuronal networks even in the absence of AD.

In their conclusions, the authors speculate that therapies which block the network effects of APP may be helpful for both seizures and cognitive impairment. As some AEDs worsen seizures in their models (as well as in humans), the efficacy of currently available treatments is called into question. The authors speculate that future therapies, perhaps targeted to abnormal proteins, may be more effective than therapies already available.

This paper is rather complex, but the implications are important. Seizures in AD cause significant morbidity. Treatment with current AEDs is often disappointing. New therapies may be required to address seizures in AD with more consistent efficacy and effectiveness, and protein network effects may be appropriate targets. It appears that we have some distance yet to travel on this road.