Epilepsy is defined by recurrent, unprovoked seizures resulting from abnormal electrical discharges in the brain. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in memory and other cognitive functions. While traditionally studied as separate diseases, mounting evidence points to a significant overlap between them, particularly in the aging brain. Researchers are investigating whether AD pathology can induce seizures and, conversely, if seizure activity accelerates the neurodegenerative process associated with AD. This complex interaction between neuronal hyperexcitability and progressive cognitive decline is a major focus of current neurological research.
Defining the Clinical Relationship
The co-occurrence of epilepsy and Alzheimer’s disease (AD) is recognized as a bidirectional relationship, where each condition increases the risk for the other. Clinical studies show that individuals diagnosed with AD are at a significantly increased risk of developing epilepsy compared to age-matched individuals without the disorder. In some populations, the risk of having a seizure is up to 6.5 times higher for those living with AD. This suggests that the biological changes characteristic of AD create an environment susceptible to abnormal electrical activity.
The reverse is also observed: people who experience late-onset epilepsy of unknown cause have an elevated probability of developing mild cognitive impairment and dementia later in life. Recurrent seizures, particularly those beginning in older adulthood, can serve as an early indicator of an underlying neurodegenerative process. The clinical link is especially strong in patients with early-onset AD, who show a higher rate of seizures than those with the more common late-onset form.
How Alzheimer’s Pathology Drives Seizures
The pathology of Alzheimer’s disease directly promotes neuronal hyperexcitability, the biological basis for seizures. This process begins with the accumulation of abnormal proteins, specifically amyloid-beta (Aβ) peptides. Soluble forms of Aβ are particularly toxic to synapses, the communication points between neurons. These toxic Aβ oligomers destabilize neural networks, leading to an imbalance between excitatory and inhibitory signals.
The brain normally maintains a precise balance between signals that excite neurons (mediated by glutamate) and signals that inhibit them (mediated by GABA). In the AD brain, Aβ disrupts inhibitory neurons and their connections, effectively reducing the “brakes” on the neural network. This disruption shifts the network toward excessive excitation, making neurons prone to firing uncontrollably. The hippocampus, a memory region severely affected early in AD, is particularly vulnerable to this hyperexcitability.
This excessive electrical activity often manifests as “silent seizures” or subclinical epileptiform discharges, which are not outwardly noticeable as convulsions but are detectable on an electroencephalogram (EEG). These silent discharges, found in a substantial percentage of AD patients, are linked to faster rates of cognitive decline. The other hallmark protein of AD, hyperphosphorylated tau, also contributes to this pathology by affecting neuronal structure and transport, further destabilizing the network and lowering the seizure threshold.
Epilepsy’s Influence on Cognitive Decline
Recurrent seizure activity, even without a primary AD diagnosis, can accelerate neurodegeneration and lead to cognitive decline. Each seizure episode involves an uncontrolled burst of electrical energy that overwhelms brain cells. This excessive firing causes excitotoxicity, where neurons are damaged or destroyed by overstimulation, primarily from the excessive release of glutamate.
Chronic seizures induce long-term structural changes, most notably the loss of neurons in the hippocampus. This damage impairs the brain’s ability to form new memories and accelerates the progression of existing cognitive impairment. Furthermore, seizures trigger a sustained inflammatory response known as neuroinflammation. Immune cells like microglia become chronically activated, releasing damaging molecules that perpetuate neuronal injury.
This inflammatory and excitotoxic environment is hypothesized to promote the accumulation of Alzheimer’s pathology. Seizure activity increases the production of amyloid-beta and accelerates the hyperphosphorylation of tau protein in animal models and human tissue. This creates a vicious cycle where seizures worsen the neurodegenerative environment, making the brain more susceptible to future seizures and further cognitive decline. Patients with AD who experience seizures often show a more rapid deterioration of cognitive functions.
Shared Genetic and Biological Vulnerabilities
Beyond the direct causal links, shared genetic and biological vulnerabilities predispose individuals to both epilepsy and Alzheimer’s disease (AD). Both disorders are characterized by a failure of brain network homeostasis, meaning the brain loses its ability to maintain stable electrical activity. This shared instability suggests some people possess a biological makeup that makes their neural networks fragile to excitotoxic damage and protein aggregation.
A notable shared genetic risk factor is the apolipoprotein E epsilon 4 (APOE \(\epsilon4\)) allele. While APOE \(\epsilon4\) is the most significant genetic risk factor for late-onset AD, it also increases the risk for developing epilepsy, particularly temporal lobe epilepsy. The presence of this allele may make neurons less resilient to the damage caused by chronic hyperexcitability.
Other common pathways include neuroinflammation and vascular health issues. Chronic systemic inflammation and poor cerebrovascular health, such as that caused by hypertension or stroke, are recognized risk factors for both AD and late-onset epilepsy. These factors compromise the brain’s environment and its defenses, making it more vulnerable to the pathologies that lead to network dysfunction. These shared vulnerabilities underscore the view of epilepsy and AD as disorders with overlapping roots in brain network instability and neurobiological stress.