Sporadic late-onset Alzheimer's disease (LOAD) is a multifactorial disease with distinct cognitive and histopathological subtypes and is the most common cause of dementia. There is growing evidence of a link between Alzheimer's disease (AD) and epilepsy. In the first few years of cognitive decline in AD patients, late-onset epilepsy and epileptiform activity may occur, the presence of which also indicates a faster course of the disease. Pathologic signs of AD include extracellular amyloid β (Aβ) plaques and intraneuronal aggregates of hyperphosphorylated tau (p-tau) protein. In animal models of Alzheimer's disease, Aβ and p-tau proteins cause pathological cortical hyperexcitation and seizures. Therefore, as a potentially controllable risk factor for dementia, the detection of epileptiform activity in AD is of great clinical significance.
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Epidemiological relationship between AD and epilepsy
The incidence of epilepsy increases after the age of 50 and is highest in people over the age of 65. Late-onset epilepsy (LOE) occurs in people over the age of 55 and is the third most common neurological disorder in older adults, after stroke and dementia. Studies have found that people with LOE have a 2-3 times higher risk of seizures of dementia compared to their peers without epilepsy. Pooled results showed that the risk of LOE associated with AD was as high as 2.4 times.
· AD with late-onset epilepsy of unknown etiology
A retrospective analysis of 2367 patients with epilepsy after age 50 years found that the most common risk factor for LOE was stroke, which occurred in 31% to 45% of people aged 60 years or older. The second most common risk factors are neoplasm (10% to 16%) and dementia (9% to 18%). In up to 41% of patients with LOE, the cause is unknown, and it is called LOE of unknown etiology (LOEU).
The neurodegenerative process that precedes the clinical seizure of LOAD can be up to 10-20 years, so neuropathic changes may already be present at the time of the patient's first seizure. This conclusion is supported by retrospective findings, which show that cognitive decline is detected in more than half of patients with LOEU, and that LOEU may be an early sign of neurodegeneration.
Previous studies have shown that patients with LOEU have decreased levels of Aβ and increased levels of p-tau in the cerebrospinal fluid (CSF) compared with authors without seizures of comparable age, which is consistent with the levels of AD patients, suggesting that LOEU patients have AD-specific neurodegenerative processes.
In a prospective study, 37.5% of dementia-free LOEUU patients had pathological Aβ CSF levels at baseline, and these patients were 3.4 times more likely to develop AD during the 3-year follow-up compared with healthy individuals. Other studies have shown that LOEU patients with mild cognitive impairment (MCI) have significantly lower levels of Aβ CSF compared to LOEU patients without cognitive impairment. In addition, Sweden's first national study of cerebrospinal fluid biomarker analysis, which included 17,901 patients with AD with or without epilepsy, found an association between epilepsy and more severe Aβ and tau lesions, suggesting that epilepsy is more common in AD patients with more pronounced neurodegeneration.
· Epilepsy in patients with LOAD
Two prospective community studies published in 2018 and 2020 showed that patients with unspecified types of dementia had a 2-3 times higher risk of developing epilepsy. A 2021 meta-analysis of 27 observational studies assessing the risk of seizures in patients with dementia showed that the overall relative risk of seizures in patients with LOAD was 3.4 times higher than that in healthy individuals. Coincidentally, a 2022 meta-analysis of 20 longitudinal studies found that patients with AD had a 3.1-fold risk of developing epilepsy compared with those without AD.
Previous observational studies have also shown that patients with a longer course of AD have a higher risk than those with a shorter course of disease. In addition, poor cognitive status also increases the risk of seizures. The risk of seizures due to previous stroke, hypertension, smoking, diabetes, or hyperlipidemia leading to cardiovascular and cerebrovascular disease is higher than that of people without such disorders.
In addition, epilepsy accelerates the rate of cognitive deterioration in patients with LOAD. A 2019 prospective study found that patients with mild LOAD with epilepsy deteriorated at a rate of 4 times faster than those without epilepsy during a 12-month follow-up period.
Subclinical epileptiform activity in patients with LOAD
Subclinical epileptiform activity (SEA) has been shown to be common in patients with LOAD and can accelerate disease progression. SEA is epileptiform activity, including spikes and sharp waves, detected in electroencephalogram (EEG) in people with unclinically determined seizures, and has a morphology similar to that of interictal epileptiform discharges (IEDs) in people with epilepsy. Like IEDs, SEA also marks hyperexcitability caused by imbalances of excitation and inhibition in neuronal networks affected by neurodegeneration.
A 2021 meta-analysis of 26 studies found that the cumulative incidence of SEA was 21% in 721 patients with LOAD. EEG testing has found that SEA occurs in 21% to 54% of patients with LOAD, compared with 5% to 25% in healthy patients. A small magnetoencephalography study detected SEA in 42% of patients with LOAD, compared with 11% in healthy individuals. In addition, a polysomnography study found SEA in 11.6% of patients with AD-induced MCI and 4.5% of healthy individuals, suggesting that hyperexcitability may occur in the early stages of LOAD.
In addition, the prevalence of SEA increases with the severity of the disease. In one study, SEA was present in 16.7% of patients with very mild dementia, 19.8% of patients with mild dementia, 23.4% of patients with moderate dementia, and 33.3% of patients with severe dementia. These results suggest that increased hyperexcitability is associated with severe neurodegeneration.
A study exploring the cognitive function of SEA in dementia reported that after 3 years of follow-up, LOAD patients with SEA experienced 2.5 times faster memory decline and executive function deteriorated 8 times faster than LOAD patients without SEA. In a large cohort of patients with LOAD, patients with SEA deteriorated 2.3-fold faster at baseline to 1-year follow-up compared with those without SEA. Other studies have found that the more spikes on baseline EEG, the worse the cognitive follow-up score, suggesting that hyperexcitement is associated with the rate of cognitive decline. In addition, cognitive decline in LOAD patients with SEA was 5 to 6 years earlier than in LOAD patients without LOAD.
Treatment of seizures in AD patients
In 2020, the European Society of Neurology published guidelines for the medical management of dementia. Guidelines recommend that a single unprovoked seizure in patients with dementia should be considered structural epilepsy, and that the disorder should be treated given the evidence that untreated seizures can lead to accelerated cognitive decline. Guidelines further recommend levetiracetam or lamotrigine as initial antiepileptic drugs (ASMs) that are well tolerated.
When choosing ASM for the treatment of seizures in patients with AD, consideration should be given to the potential cognitive negative effects of treatment. Cognitive adverse effects of first-generation ASM (including phenobarbital, primidone, and phenytoin) are more common than second-generation drugs such as gabapentin, lamotrigine, lacosamide, and levetiracetam. When using ASMs, it is critical to minimize dose-dependent adverse effects (e.g., cognition, gait, sedation, tremor, dizziness, visual disturbances, worsening of mood or irritability). Seizures in older adults can usually be controlled with low-dose antiseizure medications to minimize adverse effects. Non-enzymatic induction of ASM is preferred to reduce drug-drug interactions.
· Levetiracetam
A mouse model demonstrates that levetiracetam normalizes seizure-induced neurogenetic alterations, reverses or prevents microglial dysfunction, reduces amyloid plaque burden, inhibits hippocampal neuronal loss, and restores alterations of Aβ and p-tau in the hippocampus.
Although levetiracetam treatment did not improve overall executive function scores compared with placebo in a 2021 clinical trial in AD patients, in an exploratory subgroup analysis, there was a significant improvement in both the Stroop nomenclature subscale and the virtual route learning test in patients with epileptiform activity on EEG compared with placebo. In addition, a 2023 double-blind placebo-controlled study in AD patients showed that levetiracetam increased hippocampal blood flow. In summary, the available clinical evidence suggests that levetiracetam is an effective and safe option for patients with Alzheimer's disease.
· Novel antiepileptic drugs
Previous studies in rodent models of AD have shown that cannabidiol has been approved for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis, reducing the accumulation of Aβ and p-tau and improving glucose metabolism. In addition, the drug reduces Aβ-induced neuroinflammation, reactive oxidative response, and neuronal death, thereby reversing cognitive deficits and improving memory. These results suggest that cannabidiol has the potential to treat AD.
In addition, certain ASMs may also work by increasing GABAergic inhibition in the brain. Multi-target and combination drug therapy may become an important modality for the treatment of AD-related epilepsy.
· Problems in treatment
A common misconception is that seizures in AD patients can be easily controlled with ASM. Although seizure-free is the ultimate goal of treatment for any seizure disorder, only about 70% of all people with epilepsy achieve the goal after taking ASM.
Similar to medial temporal lobe epilepsy, high rates of resistance to ASM have been reported in AD patients that far outweigh the 25% to 30% rates reported for other epilepsy. Similarly, AD mouse models are less responsive to ASM (e.g., levetiracetam and lamotrigine) during seizures.
Seizures in AD patients are a difficult condition to treat. The results of studies on various ASMs for the treatment of AD-associated seizures suggest that levetiracetam is one of the most promising compounds. However, levetiracetam carries a risk of psychiatric and behavioural adverse effects, especially at high doses and in older adults, and should be taken into account when treating. In conclusion, research is still needed to elucidate the effects of ASM (including newer ASMs such as cannabidiol) on cognitive decline in AD patients.
summary
Previous studies have shown that cortical hyperexcitability is more common in AD patients and affects the pathophysiological process of the disease. Seizures exacerbate Aβ and p-tau protein deposition, leading to hyperexcitability of AD neurons and deterioration of cognitive function. More than half of patients with LOEU have MCI at the time of their first seizure, thus raising the question of whether epilepsy is a non-cognitive precursor to AD. This result highlights the importance of early cognitive screening for LOEU patients to ensure timely access to disease-modifying interventions.
SEA is more prevalent in patients with LOAD and is associated with an increased rate of cognitive decline. The higher the number of spikes, the worse the patient's cognitive ability, indicating a direct correlation between cortical pathological hyperexcitation and deterioration of memory function. Clinical recognition of seizures in AD patients is often difficult, and nocturnal EEG is highly sensitive for detecting epileptiform events, so it is recommended early in the diagnostic work-up for AD to ensure timely and appropriate ASM therapy if necessary.
医脉通编译自：Kamondi A, Grigg-Damberger M, Löscher W, et al. Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps, and conundrums. Nat Rev Neurol. 2024 Mar; 20（3）:162-182. doi: 10.1038/s41582-024-00932-4. Epub 2024 Feb 14. PMID: 38356056.
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