A perfect storm: Converging paths of epilepsy and Alzheimer’s dementia intersect in the hippocampal formation

Seizures in the human temporal lobe transiently impair cognition and steadily damage hippocampal circuitry, leading to progressive memory loss. Similarly, the toxic accumulation of Aβ peptides underlying Alzheimer’s disease (AD) triggers synaptic degeneration, circuit remodeling, and abnormal synchronization within the same networks. Because neuronal hyperexcitability amplifies the synaptic release of Aβ, seizures create a vicious spiral that accelerates cell death and cognitive decline in the AD brain. The confluence of hyperexcitability and excitotoxicity, combined with the challenge of seizure detection in the human hippocampus, make epilepsy in these individuals extremely important to correctly diagnose and treat. Emerging clinical evidence reveals an elevated comorbidity of epilepsy in AD, particularly when linked to mutations in the APP/Aβ gene pathway. Experimental models in genetically engineered mice confirm and extend these findings, highlighting the presence of subclinical seizures and overlapping pathophysiologic cascades. There is an urgent need for more clinical and basic investigation to improve the early recognition of hippocampal seizures arising during the course of dementing disorders, and to validate molecular blockers of Aβ‐induced aberrant excitability that can slow and potentially reverse the progression of cognitive decline.