Alzheimer Disease and Epilepsy: A Mendelian Randomization Study

Backgroundand ObjectivesObservational studies suggested a bidirectional relationship between Alzheimer’s disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. The present study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (Aβ42, pTau) and epilepsies with two-sample, bi-directional Mendelian randomization (MR) method.MethodsGenetic instruments were obtained from large-scale genome-wide meta-analysis of AD (Ncase/proxy= 111,326, Ncontrol= 677,663), CSF biomarkers of AD (Aβ42 and pTau, N = 13,116) and epilepsy (Ncase= 15,212, Ncontrol= 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, and lesion-negative focal epilepsy. Main analyses were performed using generalized summary data-based mendelian randomization (GSMR). Sensitivity analyses included IVW, MR-PRESSO, MR-Egger, weighted mode, and weighted median.ResultsFor forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (OR = 1.053, 95% CI: 1.002 ∼ 1.105,P= 0.038), and focal epilepsy with hippocampal sclerosis (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 instrumental SNPs from another AD GWAS. For reverse analysis, there was a suggestive effect of focal epilepsy with hippocampal sclerosis 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).DiscussionThe present MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal epilepsy with hippocampal sclerosis. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.