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

Altres ajuts: Fondo de Investigaciones Sanitario (FIS); National Institutes of Health (1R01AG056850-01A1, R21AG056974, R01AG061566); Fundació La Marató de TV3 (20141210); Sociedad Catalana de Neurología (SCN-2020 to MCI); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Luca; Fundación Tatiana Pérez de Guzmán el Bueno.Epilepsy and Alzheimer's disease (AD) incidence increases with age. There are recip-rocal 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 anato-mopathological 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 epilepti-form 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