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. 2023 Nov;13(11):e3221.
doi: 10.1002/brb3.3221. Epub 2023 Sep 4.

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study

Lianping Xu  1   2 , Qun Wang  1   2   3
Affiliations

The bidirectional relationship between Alzheimer's disease (AD) and epilepsy: A Mendelian randomization study

Lianping Xu et al. Brain Behav. 2023 Nov.

Abstract

Background: There is a complex, bidirectional relationship between Alzheimer's disease (AD) and epilepsy. However, the causality of this association is unclear, as confounders play a role in this association.

Methods: We conducted a Mendelian randomization (MR) study to clarify the causal relationship and direction of epilepsy on AD risk. We used publicly available summary statistics to obtain all genetic datasets for the MR analyses. AD and AD-by-proxy and late-onset AD (LOAD) cohorts were included in our study. The epilepsy cohort comprised all epilepsy, generalized epilepsy, focal epilepsy, and its subtypes, as well as some epilepsy syndromes. Next, we conducted validation using another AD cohort.

Results: Two correlations between AD and epilepsy using the inverse variance-weighted (IVW) method are as follows: LOAD and focal epilepsy (ORIVW = 1.079, pIVW = .013), focal epilepsy-documented hippocampal sclerosis (HS) and AD (ORIVW = 1.152, pIVW = .017). The causal relationship between epilepsy-documented HS and AD has been validated (ORIVW = 3.994, pIVW = .027).

Conclusions: Our MR study provides evidence for a causal relationship between focal epilepsy-documented HS and AD.

Keywords: Alzheimer's disease; Alzheimer's disease (late onset) (load); Mendelian randomization; epilepsy; focal epilepsy.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The process of the Mendelian randomization (MR) study. “a” Alzheimer's disease, Alzheimer's disease (late onset) (LOAD), “b” epilepsy (genome‐wide association studies [GWAS] ID: ieu‐b‐8), genetic generalized epilepsy (ieu‐b‐9), focal epilepsy (ieu‐b‐10), focal epilepsy‐documented lesion negative (ieu‐b‐11), juvenile absence epilepsy (ieu‐b‐12), childhood absence epilepsy (ieu‐b‐13), focal epilepsy‐documented hippocampal sclerosis (ieu‐b‐14), focal epilepsy‐documented lesions other than hippocampal sclerosis (ieu‐b‐15), generalized epilepsy with tonic–clonic seizures (ieu‐b‐16), and juvenile myoclonic epilepsy (ieu‐b‐17). SNP, single‐nucleotide polymorphism.
FIGURE 2
FIGURE 2
Scatter plot of potential effects of Alzheimer's disease (AD) and epilepsy. The slope of each line corresponds to the estimated Mendelian randomization (MR) effect of each method: (A) scatter plot of AD (late onset) (LOAD) on focal epilepsy (ieu‐b‐10), (B) scatter plot of focal epilepsy‐documented hippocampal sclerosis (ieu‐b‐14) on AD. IVW, inverse variance‐weighted; MR‐Egger, Mendelian randomization‐Egger; SNP single nucleotide polymorphisms.
FIGURE 3
FIGURE 3
Leave‐one‐out sensitivity analysis for late‐onset Alzheimer's disease (LOAD) and focal epilepsy. Each row (black lines) represents the result after the removal of the corresponding single nucleotide polymorphism (SNP), and the overall effect is shown at the bottom (redline).
See this image and copyright information in PMC

References

    1. Alzheimer's Association . (2016). 2016 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 12(4), 459–509. 10.1016/j.jalz.2016.03.001 - DOI - PubMed
    1. Amatniek, J. C. , Hauser, W. A. , Delcastillo‐Castaneda, C. , Jacobs, D. M. , Marder, K. , Bell, K. , Albert, M. , Brandt, J. , & Stern, Y. (2006). Incidence and predictors of seizures in patients with Alzheimer's disease. Epilepsia, 47(5), 867–872. 10.1111/j.1528-1167.2006.00554.x - DOI - PubMed
    1. Annegers, J. F. , Dubinsky, S. , Coan, S. P. , Newmark, M. E. , & Roht, L. (1999). The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance organizations. Epilepsia, 40(4), 502–506. 10.1111/j.1528-1157.1999.tb00748.x - DOI - PubMed
    1. Bellenguez, C. , Küçükali, F. , Jansen, I. E. , Kleineidam, L. , Moreno‐Grau, S. , Amin, N. , Naj, A. C. , Campos‐Martin, R. , Grenier‐Boley, B. , Andrade, V. , Holmans, P. A. , Boland, A. , Damotte, V. , Van Der Lee, S. J. , Costa, M. R. , Kuulasmaa, T. , Yang, Q. , De Rojas, I. , Bis, J. C. , … Lambert, J.‐C. (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genetics, 54(4), 412–436. 10.1038/s41588-022-01024-z - DOI - PMC - PubMed
    1. Bowden, J. , Davey Smith, G. , Haycock, P. C. , & Burgess, S. (2016). Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiology, 40(4), 304–314. 10.1002/gepi.21965 - DOI - PMC - PubMed

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