Alzheimer Disease and Epilepsy: A Mendelian Randomization Study

BACKGROUND AND OBJECTIVES: Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. This study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (β-amyloid [Aβ] 42 and phosphorylated tau [pTau]), and epilepsies with 2-sample, bidirectional Mendelian randomization (MR) method. METHODS: Genetic instruments were obtained from large-scale genome-wide meta-analysis of AD (N(case/proxy) = 111,326, N(control) = 677,663), CSF biomarkers of AD (Aβ42 and pTau, N = 13,116), and epilepsy (N(case) = 15,212, N(control) = 29,677) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy, focal epilepsy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with tonic-clonic seizures, focal epilepsy with hippocampal sclerosis (focal HS), and lesion-negative focal epilepsy. Main analyses were performed using generalized summary data-based MR. Sensitivity analyses included inverse variance weighted, MR pleiotropy residual sum and outlier, MR-Egger, weighted mode, and weighted median. RESULTS: For forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (odds ratio [OR] 1.053, 95% CI 1.002–1.105, p = 0.038) and focal HS (OR 1.013, 95% CI 1.004–1.022, p = 0.004). These associations were consistent across sensitivity analyses and replicated using a separate set of genetic instruments from another AD genome-wide association study. For reverse analysis, there was a suggestive effect of focal HS on AD (OR 3.994, 95% CI 1.172–13.613, p = 0.027). In addition, genetically predicted lower CSF Aβ42 was associated with an increased risk of generalized epilepsy (β = 0.090, 95% CI 0.022–0.158, p = 0.010). DISCUSSION: This MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal HS. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.