Mechanisms Involved in Epileptogenesis in Alzheimer’s Disease and Their Therapeutic Implications

Abstract

Epilepsy and Alzheimer’s disease (AD) incidence increases with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age, and abnormal AD biomarkers in PET and/or CSF are frequently found in late-onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes, including neuronal hyperexcitability and an early excitatory–inhibitory dysregulation, leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies, suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy, share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology, such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate the progression of cognitive decline, and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly patients without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with an altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASMs). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.

Assessment of tau phosphorylation and β‐amyloid pathology in human drug‐resistant epilepsy

“…The accumulation of Aβ plaques and NFT can disrupt neural function and promote neurodegeneration leading to cognitive decline and dementia, 13 neuronal hyperexcitability 14,15 and seizures. 11,16 Contemporary evidence supports that the occurrence of epilepsy is higher in AD patients with severe dementia. 11 The reported incidence of unprovoked seizures or epileptiform activity in AD patients varies in different studies ranging from a low of 9%-10% 17,18 to a high of 16%-38%.…”

“…Histopathological hallmarks of AD include the accumulation of β‐amyloid (Aβ) plaques and the presence of neuropil threads (NT), or neurofibrillary tangles (NFT) formed by the aggregation of hyperphosphorylated tau protein (p‐tau). The accumulation of Aβ plaques and NFT can disrupt neural function and promote neurodegeneration leading to cognitive decline and dementia, 13 neuronal hyperexcitability 14,15 and seizures 11,16 . Contemporary evidence supports that the occurrence of epilepsy is higher in AD patients with severe dementia 11 .…”

The clinical correlation between Alzheimer's disease and epilepsy

“…Thus, there is a bi-directional association between AD and epilepsy. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age (9). Many studies have evaluated the shared pathogenesis and clinical relevance of AD and epilepsy (5,10,11).…”

Deep brain stimulation of fornix in Alzheimer's disease: From basic research to clinical practice

“…77 Hippocampal electrical activity during high-frequency stimulation above 45 Hz can inhibit seizures originating from hippocampus, 78 while low-frequency (1 Hz) stimulation of the fornix in patients with temporal lobe epilepsy improved the delayed memory performance of MMSE. 61 Based on the fact that epileptic seizures or even subclinical epileptic discharges significantly can accelerate the process of Aβ deposition and cognitive impairment in AD patients, 79 treatment effect of fornix DBS on cognition may be related to its modulation to the hippocampal circuits. The pulse width is selected according to the experience of PD-DBS treatments.…”