Alzheimers Risk Tied to Epilepsy Risk, and Vice Versa

A genetic predisposition for Alzheimer’s disease (AD) has been associated with an increased risk of epilepsy, and vice versa, results of a large genome-wide association study (GWAS) show.

“Our research found that not only are people with Alzheimer’s disease more likely to develop epilepsy but also that those with focal epilepsy, which accounts for more than half of all cases of epilepsy, were more likely to develop Alzheimer’s disease,” study investigator Jiali Pu, PhD, of Zhejiang University School of Medicine, Hangzhou, China, said in a press release.

“More effort should be made to screen for seizures in people with Alzheimer’s disease and to understand the impact of seizures on those facing these two challenging conditions,” Pu added.

The study was published online May 24 in Neurology.

Vicious Cycle

“Accumulating evidence indicates a close association between AD and epilepsies” with preclinical studies suggesting a “vicious cycle” between them, the investigators note.

Amyloid-beta has demonstrated epileptogenic potential, even in early stages of the amyloid cascade. On the other hand, epileptiform activity and chronic hyperexcitability may promote amyloid plaque deposits and tau hyperphosphorylation.

Human studies have pointed to a bidirectional association of epilepsy with AD. Given this close relationship, the investigators note that it is “essential to verify a true causal association, as such an association would indicate a potentially modifiable cause or previous underrecognized consequence of AD.”

The researchers chose Mendelian randomization (MR) methodology because it “minimizes several inherent limitations of conventional observation studies, including unobserved confounding and reverse causality.”

The current study utilized two-sample MR analyses, testing the hypotheses that AD drives epilepsy and that epilepsy drives AD. The researchers also studied the association between genetically predicted cerebrospinal fluid (CSF) markers of AD (amyloid-beta 42 and pTau) and epilepsy.

“Novel Evidence”

The investigators drew on GWAS summary statistics for epilepsy and subtypes from the International League Against Consortium on Complex Epilepsies (n = 15,212 cases and 29,677 controls). Phenotype categories included genetic generalized epilepsy, focal epilepsy (focal sclerosis, lesion other than HS, lesion-negative, and not otherwise specified), and unclassified epilepsy.

They also drew on data from an AD GWAS meta-analysis, which included patients with AD as well as proxy cases — ie, people with a family history of AD (n = 111,325 cases and proxies and 667,663 controls). To replicate positive findings, they used an earlier GWAS dataset that only enrolled late-onset AD cases.

Genetic predictors of CSF AD markers were obtained from the European Alzheimer and Dementia Biobank (n = 13,116 European ancestry individuals).

Genetic predisposition to AD was associated with a higher risk of focal hippocampal sclerosis (HS) (odds ratio, 1.013; 95% CI, 1.004 – 1.022; P = .004) — a finding replicated in sensitivity analyses.

AD was also associated with an elevated risk of generalized epilepsy (OR, 1.053; 95% CI, 1.003 – 1.105; P = .038), with sensitivity analyses yielding similar estimates in magnitude and direction.

The forward analysis (the effect of epilepsy on AD) showed a significant effect of focal HS on AD (OR, 3.994; 95% CI, 1.172 – 13.613; P = .027). But when the researchers attempted to replicate this finding using the other datasets, the estimated effect was not significant and, in fact, went in the opposite direction (P = .252).

Genetically predicted lower CSF amyloid-beta 42 was associated with a higher risk of generalized epilepsy (β = .090; 95% CI, 0.022 ~ 0.158; P = .010), with similar estimates found in sensitivity analyses.

There was no significant effect of epilepsy on CSF biomarkers.

A limitation of the study is that participants were of European ancestry, so the results may not be generalizable to other populations.

The authors conclude that they’ve provided “novel evidence that AD was causally linked to generalized epilepsy and focal epilepsy with hippocampal sclerosis.”

Confusing Nomenclature

Commenting for Medscape Medical News, Percy Griffin, PhD, Alzheimer’s Association director of science engagement, called it “intriguing work, suggestive of possible treatment and prevention strategies that may be worth pursuing.”

However, it “does not have immediate clinical implications until it is replicated and confirmed in additional, more representative study populations,” said Griffin, who was not involved with the study. He noted that current trials are investigating anti-seizure medications as possible treatments for AD.

Also commenting for Medscape Medical News, Jacqueline French, MD, professor of neurology, NYU Comprehensive Epilepsy Center, New York City, expressed concerns about the study.

“In the ‘discussion’ section, the authors say that generalized epilepsy ‘has been observed in 15% to 40% of patients with Alzheimer’s at various disease stages,’ but this is incorrect,” said French, chief medical and innovation office for the Epilepsy Foundation of America, who was not involved with the study.

She explained that there’s a difference between “generalized seizures” — ie, tonic-clonic seizures, which have been renamed “focal-to-bilateral” or “tonic-clonic bilateral” — vs “generalized epilepsy,” which is idiopathic and rarely presents late in life, such as when a person might develop AD.

“Most seizures that occur in people with Alzheimer’s are focal, not generalized, and they don’t have ‘generalized epilepsy,’ ” she explained.

She agrees that there is a potential bidirectional link between AD and focal HS, “which makes more sense.”

However, French said the study’s take-home message for patients with epilepsy is not that they will likely go on to develop AD.

On the other hand, people with AD “have brains that are more hyperexcitable, which is a risk factor for seizures, and there is some evidence suggesting people with AD are at higher risk for focal epilepsy, but it’s unlikely to come from a genetic predisposition,” she said.

This study was supported by the National Natural Science Foundation of China and the Key Research and Development Program of Zhejiang Province. The authors, Griffin, and French disclose no relevant financial relationships.

Neurology. Published online May 24, 2023. Abstract

Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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