The Bidirectional Relationship Between Epilepsy and Alzheimer's Disease

Epilepsy has long been considered a late-stage consequence of Alzheimer's Disease (AD), but recent studies highlight its role early in the disease process, even preceding cognitive symptoms. Population studies reveal a two- to fourfold increased epilepsy risk in AD, particularly in early-onset cases, with seizures clustering around diagnosis. Furthermore, individuals with late-onset unexplained epilepsy have an elevated risk of developing mild cognitive impairment and dementia, underscoring a bidirectional relationship between AD and epilepsy.

Experimental models support this connection, demonstrating amyloid and tau pathology-induced hyperexcitability at pre-symptomatic stages, implicating soluble Aβ oligomers and inhibitory interneuron dysfunction in excitatory/inhibitory imbalance. Subclinical or clinical epileptiform activity, detectable in 20-50% of AD patients, is associated with cognitive decline, possibly due to sleep-related memory consolidation disruption. Emerging biomarkers, such as TIRDA and high-frequency oscillations, show promise for early detection and intervention. Anti-seizure medications (ASMs), particularly low-dose levetiracetam, show potential not only for seizure control but also for mitigating amyloid deposition, tau hyperphosphorylation, and cognitive decline. However, treatment complexities remain due to variable ASM efficacy, age-related side effects, and limited clinical trials. The bidirectional nature of AD and epilepsy emphasizes the need for integrated diagnostics, including EEG and biomarker assessments, to guide early intervention and targeted therapies. Future research should focus on the mechanistic interplay between amyloid, tau, and hyperexcitability, alongside trials of ASM regimens, to refine therapeutic strategies and improve outcomes in this population.