APOE4 Allele Carriers and Parkinson Disease Named Among Highest Risk Factors for Epilepsy in Patients With Dementia

Author(s):

Key Takeaways

APOE e4 allele, early-onset dementia, Alzheimer's subtype, stroke/TIA, severe dementia, and Parkinson's disease increase epilepsy risk in dementia patients.
Study involved 15,582 participants, with 1.6% developing epilepsy; non-significant factors included education, race, and hypertension.
Previous research showed dementia patients with seizures have worse cognition, higher mortality, and increased physical dependence.
Early recognition and treatment of subtle seizures in dementia patients are vital for effective management and improved outcomes.

Factors like education level, hypertension, diabetes, and depression did not significantly predict epilepsy risk in patients with dementia.

Ifrah Zawar, MD

A study presented at the 2024 American Epilepsy Society (AES) annual meeting, held December 6-10 in Los Angeles, California, identified specific predictors of epilepsy in patients with dementia (PWD). All told, patients with the apolipoprotein (APOE) e4 allele, those with dementia-onset before the age of 60, Alzheimer disease (AD) subtype of dementia, stroke/transient ischemic attack (TIA), severe dementia, and Parkinson disease (PD) were among the highest risk.¹

This longitudinal, multicohort study included 15,582 participants with dementia and mild cognitive impairment recruited from 39 AD centers in the US from 2005 to 2021. These participants had at least 2 visits without epilepsy, did not have active epilepsy, or remote seizures at enrollment. During follow-up, 254 (1.6%) patients developed epilepsy, otherwise considered the primary outcome.

Led by Ifrah Zawar, MD, an assistant professor of neurology at the University of Virginia, investigators conducted a multivariable survival analysis to study the predictors of epilepsy in PWD. After adjusting for demographics, cardiovascular risk factors, neurologic comorbidities, genetics, cognitive status, and depression, those with the presence of APOE4 heterozygous or homozygous allele (adjusted hazard ratio [aHR], 1.35; 95% CI, 1.03-1.78; P = .0289), cognitive decline-onset before the age of 60 (aHR, 2.25; 95% CI, 1.44-3.55; P <.0004), AD as the subtype of dementia (aHR, 1.65; 95% CI, 1.15-2.38; P <.0069), severe dementia (aHR, 2.13; 95% CI, 1.86-2.44; P <.001), stroke or TIA (aHR, 1.98; 95% CI, 1.34-2.92; P = .0006), and presence of PD (aHR, 2.39; 95% CI, 1.02-5.58; P = .0437) were at a higher risk of developing epilepsy.

Other risk variables studied that were not significant included education level (aHR, 0.99; 95% CI, 0.95-1.03), White race (aHR, 1.18; 95% CI, 0.79-1.75), Hispanic ethnicity (aHR, 0.76; 95% CI, 0.45-1.29), and hypertension (aHR, 0.96; 95% CI, 0.72-1.29). Similarly, things like diabetes (aHR, 0.88; 95% CI, 0.55-1.43), hypercholesterolemia (aHR, 0.78; 95% CI, 0.55-1.43), dominant AD mutation (aHR, 0.78; 95% CI, 0.19-3.25), traumatic brain injury (aHR, 1.08; 95% CI, 0.73-1.61), active depression (aHR, 1.03; 95% CI, 0.78-1.35), and smoking status (aHR, 1.00; 95% CI, 0.99-1.01) also did not show a significant effect.

Zawar has done previous research examining the interplay between dementia and epilepsy/seizures. A study she presented at AES 2022 using the same data set showed that patients with dementia and active seizures at a younger age have worse cognition, poorer function, and higher mortality rates in comparison to those without seizures who have dementia. In the study, at a younger age (72.99 vs 79.72 years; P <.001), a higher proportion of patients with seizures died (OR, 1.56; P <.001). Notably, even after adjustment of the model analysis, patients that had active seizures showed to be at a higher risk of dying earlier in age (HR, 1.56; 95% CI, 1.28-1.90; P <.001).²

The results showed with 26425 cognitively impaired patients at the initial visit, 374 (1.4%-point prevalence) had active seizures at baseline. Furthermore, the patients with seizures were significantly younger than (62.91 vs 68.4 years; P <.001) at the onset of cognitive decline. Also, patients with active seizures performed worse on Mini-Mental Status Examination (18.50 vs 22.88; P <.001), Clinical Dementia Rating-Sum of Boxes (7.95 vs 4.28; P <.001), and the functional assessment score after the adjustment for age and duration of cognitive decline. Notably, patients with seizures had a higher chance of having physical dependence (OR, 2.52; CI, 1.99-3.19; P <.001).

"I personally think that the most important thing in clinical practice is to identify the patients who have ongoing clinical seizures because often, seizures tend to be subtle in patients with dementia or even elderly. Otherwise, they're not what we typically perceive seizures as like the shaking seizure," Zawar told NeurologyLive in 2022, "Often, patients may just have a slight blank stare, or some episodic confusion, which can be really hard to distinguish in the setting of ongoing cognitive impairment, which is just a part of dementia. I think the most important part of the care is to recognize seizures, and treat them early on, because seizure medications do work pretty well and we can, for most parts, control seizures in this patient population."

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REFERENCES
1. Zawar I, Quigg M, Manning C, Kapur J. Predictors of Epilepsy Development in People with Dementia: A Longitudinal Multicenter Study. Presented at: 2024 AES Annual Meeting; December 6-10; Los Angeles, CA. ABSTRACT 2.218.
2. Zawar I, Quigg M, Manning C, Kapur J. Seizures in Dementia are Associated with Worse clinical outcomes, Higher Mortality and Shorter Lifespans. Presented at: AES Annual Meeting; December 2-6, 2022; Nashville, TN, and virtual. Poster352.