The bidirectional association of epilepsy with Alzheimer's disease and other neurodegenerative dementias: A longitudinal observational study on the UK Biobank

Background Converging evidence supports a bidirectional link between epilepsy and Alzheimer's disease (AD). Limited data are available regarding the association of epilepsy with frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB). Objective To estimate the bidirectional association between epilepsy and AD, FTD, and DLB in the UK Biobank, a large, multi-source healthcare dataset. Methods Epilepsy, AD, FTD, and DLB cohorts were extracted. Cox proportional-hazard models were used to compare the AD risk in the epilepsy cohort against matched controls, and the epilepsy risk in the AD cohort against matched controls. Prevalent association of epilepsy with FTD and DLB was assessed using Chi-squared/Fisher test. Results Hazard-ratio (HR) for AD in the epilepsy population versus controls was 2.5 (1.8–3.4, p < 0.001); HR increased when epilepsy was diagnosed in the sixth-seventh decade and in individuals with epilepsy carrying the APOE ε4 allele. Conversely, HR for epilepsy in AD versus controls was 14.8 (9.7–22.5, p < 0.001). Epilepsy prevalence was higher in the FTD population compared to controls, with prevalence ratio (PR) of 5.3 (2.4–11.8, p = 0.001). Epilepsy PR in DLB versus controls approached but did not achieve statistical significance (2.4, 1.0–5.7, p = 0.068). Conclusions Our findings reinforce the notion of a bidirectional association between epilepsy and AD, providing proof-of-concept that epilepsy, especially late-onset, may be successfully integrated into AD risk frameworks. Furthermore, we found a high prevalence of epilepsy in the FTD population. Careful stratification of individuals with epilepsy could offer an opportunity to identify those at higher risk of future or covert AD and neurodegeneration.