Epilepsy and Alzheimer’s Disease: Potential mechanisms for an association
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).
Section snippets
Alzheimer’s Disease
Dementia, an acquired cognitive decline that hampers activities of daily life, is the most common neurologic disease in elderly people, among whom it is mainly caused by AD (Hauser, 2013). However, AD can occur also earlier in life, especially considering genetic forms such as EOAD (Hauser, 2013), see above). Importantly, AD prevalence is higher in women, who have an higher lifetime risk of developing the disease (Nebel et al., 2018; Viña and Lloret, 2010) and are more severely cognitively
Clinical evidence for co-existence of AD and seizures
As described in paragraph 1, the relationship between AD and epilepsy has been intriguing researchers and clinicians for a long time (Vossel et al., 2017). However, studies on this topic are mainly cross-sectional or retrospective, with only a few prospective ones. Already in one of the first retrospective studies (Hauser et al., 1986), a high prevalence not only of seizures but also of myoclonus was identified in AD patients. Recent evidence from retrospective (Beagle et al., 2017; Cheng et
Mechanisms underlying the increased risk of seizures in AD
Various mechanisms connecting AD and epilepsy have been proposed and many elements involved in AD pathogenesis have been found to regulate neuronal excitability (Fig. 1). However, it has to be remembered that AD experimental models are mainly transgenic mice, which, as such, reproduce a condition similar to familiar AD in humans. Further studies are necessary as far as sporadic AD is concerned (Cretin et al., 2017).
How epilepsy may cause AD/neurodegeneration
In the previous paragraphs, the mechanisms through which AD may lead to a pro-epileptogenic state have been discussed. The reverse hypothesis, albeit less studied, is fascinating: how might epilepsy cause or worsen neurodegeneration and AD? In line with this hypothesis, it has been shown in AD transgenic mice that AED-mediated suppression of IED (which occurs early in the course of the disease) strongly improves cognitive deterioration, synaptic dysfunction and hippocampal remodeling (Sanchez
Funding
This research was funded by Italian Ministry of Health Ricerca Corrente (F.F.); and by Italian Ministry of Health Ricerca Finalizzata 2013, project code:# PE2013-02359574 (“In vivo assessment of the role of Locus Coeruleus in the development of Alzheimer's Disease and other types of Dementia”) (F.S.G.).
References (247)
- et al.
Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance
Neuroimage Clin.
(2015) - et al.
The descriptive epidemiology of epilepsy-a review
Epilepsy Res.
(2009) - et al.
Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice
Neurobiol. Dis.
(2006) - et al.
Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus
Neurobiol. Dis.
(2019) - et al.
Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy
Neurobiol. Aging
(2014) - et al.
Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures
Neurobiol. Dis.
(2005) - et al.
Monoamine neurotransmitters in resected hippocampal subparcellations from neocortical and mesial temporal lobe epilepsy patients: in situ microvoltammetric studies
Brain Res.
(2000) - et al.
Glutamate transporters regulate excitability in local networks in rat neocortex
Neuroscience
(2004) - et al.
Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia
Neurobiol. Dis.
(2008) - et al.
Synaptic activity regulates interstitial fluid amyloid-β levels in vivo
Neuron
(2005)
Epidemiological and medical aspects of epilepsy in the elderly
Epilepsy Res.
Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link?
Neurobiol. Aging
Alzheimer’s disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology
Neurobiol. Aging
Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease
Epilepsy Behav.
Transient epileptic amnesia mistaken for mild cognitive impairment? A high-density EEG study
Epilepsy Behav.
Increased seizure threshold and severity in young transgenic CRND8 mice
Neurosci. Lett.
Beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes
J. Biol. Chem.
Fever, febrile seizures and epilepsy
Trends Neurosci.
Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria
Lancet Neurol.
Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain
Lancet
Locus coeruleus noradrenaline system and focal penicillin hippocampal epilepsy: neurophysiological study
Epilepsy Res.
Region-and neurotransmitter-dependent species and strain differences in DSP–4–induced monoamine depletion in rodents
Neurodegeneration
Hyperexcitability and epileptic seizures in a model of frontotemporal dementia
Neurobiol. Dis.
The role of norepinephrine in epilepsy: from the bench to the bedside
Neurosci. Biobehav. Rev.
Activation of brain metabolism and fos during limbic seizures: the role of locus coeruleus
Neurobiol. Dis.
The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer’s disease
Brain Res. Bull.
Precision medicine and drug development in Alzheimer’s disease: the importance of sexual dimorphism and patient stratification
Front. Neuroendocrinol.
Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer’s disease HHS Public Access
Neurobiol. Aging
Epilepsy and cognition–a bidirectional relationship?
Seizure
Neuroinflammation in Alzheimer’s disease
Lancet Neurol.
AMPAR removal underlies aβ-induced synaptic depression and dendritic spine loss
Neuron
Dendritic function of tau mediates Amyloid-β toxicity in Alzheimer’s disease mouse models
Cell
Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice
Neuroscience
Cellular and Molecular Immunology
Epilepsy in the elderly: special considerations and challenges
Ann. Indian Acad. Neurol.
Mechanisms of excessive extracellular glutamate accumulation in temporal lobe epilepsy
Neurochem. Res.
Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms
Acta Neuropsychiatr.
Incidence and predictors of seizures in patients with Alzheimer’s disease
Epilepsia
Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice
J. Neurosci.
Convulsions induced by donepezil [7]
J. Neurol. Neurosurg. Psychiatry
The prevalence and clinical features of epileptic seizures in a memory clinic population
Seizure
A longitudinal study of epileptic seizures in Alzheimer’s disease
Front. Neurol.
Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline
Neuron
A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β
Brain
Relative incidence of seizures and myoclonus in Alzheimer’s disease, dementia with Lewy Bodies, and frontotemporal dementia
J. Alzheimers Dis.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years
J. Neuropathol. Exp. Neurol.
Ovarian cycle stages modulate Alzheimer-related cognitive and brain network alterations in female mice
eNeuro
Georges Marinesco and the early research in neuropathology
Neurology
Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease
Science
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FSG and LFS equally contributed to the article.