Epilepsy and Alzheimer’s Disease: Potential mechanisms for an association

Highlights

• AD patients have increased risk for seizures, particularly in familial forms of AD.

• Epilepsy may, in turn, lead to or exacerbate AD pathology and clinical symptoms.

• Seizures are difficult to identity in AD: clinical studies have several limitations.

• Subcortical structures (cholinergic nuclei and Locus Coeruleus) may be involved.

• At cellular level, Glutamate/GABA imbalance, channels and inflammation play a role.

Abstract

Alzheimer’s Disease (AD) and epilepsy are common neurological diseases. The prevalence of epilepsy in AD patients is higher than in healthy subjects, but identifying the reasons for this association, the characteristics of seizures in AD, and the implications for prognosis and treatment is challenging. The present review provides first of all an overview of the main clinical aspects of AD and epilepsy, of their reciprocal relationship, and of the challenges that identifying seizures in AD patients presents. Limitations of clinical studies addressing this topic are discussed, including their mostly prospective nature and possible selection biases. A comprehensive, mechanistic discussion on the factors that are most likely to underlie the increased risk for seizures in AD follows. These include, for instance, GABAergic and glutamatergic alterations, Aβ and Tau protein, the role of the noradrenergic nucleus Locus Coeruleus, and neuroinflammation. Finally, evidence concerning the role that epilepsy may have in exacerbating or initiating AD is reviewed. A mechanistic insight on the relationship between epilepsy and AD might have relevant implications for improving the treatment of AD patients, as well as in elucidating pathophysiological mechanisms.

Introduction

There is evidence that epilepsy occurs more frequently in Alzheimer's Disease (AD) patients than in the general population. Surprisingly, the first account of senile plaques - which are considered a hallmark of AD (Braak et al., 2011; Braak and Braak, 1991) - dates to fifteen years before the first report of a case of AD, and such plaques were first described in epileptic patients (reviewed in (Buda et al., 2009)). Remarkably, Alois Alzheimer himself (who is considered the discoverer of AD) recognized an increased prevalence of epilepsy among his patients with AD (revised in (Vossel et al., 2017)), and ever since the connection between these two pathologies has been puzzling researchers and clinicians. Early clinical studies aimed at specifically assessing the relationship between AD and epilepsy date back to the ‘50s (Letemendia and Pampiglione, 1958; Sjogren et al., 1952). Up to the ‘90s, the occurrence of seizures were described in more advanced stages of AD (Raudino, 2016). In the last decades, the concept of Mild Cognitive Impairment (MCI) has been introduced to describe subtle cognitive alterations preceding frank dementia and, in the case of MCI due to AD, sharing with AD dementia the same pathological mechanisms (Dubois et al., 2014). Also among MCI, it is now known that seizures and subclinical epileptiform activity are more frequent than in age-matched cognitively healthy controls (Sherzai et al., 2014).

In developed countries, the prevalence of both epilepsy and AD increases with age (Banerjee et al., 2009; Cloyd et al., 2006). Also for this reason, one might argue that an increased incidence of seizures in AD might be just due to the advanced age of AD patients. However, several reports have shown a higher incidence of seizures among AD patients, even though with major discrepancies. In particular, the prevalence of seizures in AD ranges from 3.5% to 64 %–64 %, according to the population studied and the type of monitoring used (Friedman et al., 2012). In line with this, several experimental studies have confirmed a reduced threshold to seizures in AD models (Palop et al., 2007; Palop and Mucke, 2010). More intriguingly, recent experimental data even suggest that hyperexcitability itself may play a role in promoting cognitive decline and increase of AD neuropathological burden and cognitive decline, as will be extensively discussed below.

Among AD subtypes, a particularly seizure-prone population might be represented by patients affected by Early Onset Alzheimer Disease (EOAD). In fact, in EOAD patients, myoclonus and seizures rates have been found to be as high as 30 % (Raudino, 2016; Vossel et al., 2017). EOAD is typically caused by abnormalities in presenilin (PS) 1, 2 or APP (Amyloid Precursor Protein) genes, and this supports a key role of amyloid in seizure susceptibility.

Thus, one might hypothesize that a self-perpetuating cycle occurs, in which AD pathology predisposes to seizures (Horváth et al., 2016), which in turn might concur to and exacerbate AD pathology (Vossel et al., 2017).