Epigraph Vol. 20 Issue 2, Fall 2018

Alzheimer’s and epilepsy: Intimate connections

At first blush, Alzheimer’s disease and epilepsy may appear to be nothing alike. The former occurs in older people and involves memory issues and other cognitive problems; the latter is characterized by seizures and affects people of all ages.

But the two conditions overlap in many ways. Both can involve problems with spatial memory and navigation, lowered glucose metabolism, cellular death and degeneration in the brain’s temporal lobe, and damage to the hippocampus.

Like people with Alzheimer’s disease, people with epilepsy can experience memory loss or confusion. As part of an aura, they may hear or see things that aren’t there. When older adults display these symptoms, they may be misdiagnosed with Alzheimer’s disease, when in fact they are having (or just had) a seizure. In older adults without a history of epilepsy, seizures are often nonconvulsive: The person may simply stop and stare for a few moments or become confused.

Andrew J. Cole
Andrew J. Cole

“The parallels between epilepsy and Alzheimer’s disease are quite striking,” said Andrew J. Cole, professor of neurology at Harvard University and head of the epilepsy group at Massachusetts General Hospital. “It’s surprising there hasn’t been more collaboration between the Alzheimer’s and epilepsy communities.”

The conditions also appear to be associated. People with Alzheimer’s disease have a high risk of developing seizures—more than 80 times the risk of people who don’t have Alzheimer’s.

A 2011 study found that people who had both epilepsy and Alzheimer’s disease had an earlier onset of cognitive problems—at about 65 years old, versus 70 in people with Alzheimer’s disease and not epilepsy. People with Alzheimer’s who had subclinical epilepsy—seizures without symptoms—started experienced cognitive problems even earlier, at an average age of 59 years.

Silent seizures in people with Alzheimer’s

In a study published last year in Nature Medicine, Cole and other researchers found subclinical seizures during sleep in two patients with early Alzheimer’s disease. The group identified the seizures using foramen ovale electrodes, which are placed inside the skull, near the temporal lobes.

In one patient, the electrodes recorded several seizures arising on the left and lasting 40-50 seconds. All occurred at night, with no clinical manifestations other than arousing her from sleep.

Cole believes that subclinical seizures are more common than previously realized. “I think they do play a role in Alzheimer’s disease,” he said. “Seizures are a form of intense neural activity, so the hypothesis that seizures might promote or accelerate or modulate the pace of Alzheimer’s seems viable.”

One study found that 42% of Alzheimer’s patients had subclinical seizure activity, compared with 11% of age-matched controls. The activity most often originated in the temporal lobe and was more common during the deeper stages of sleep. Over a 5-year period, patients with subclinical seizure activity had increased cognitive decline. However, it’s not clear if the seizure activity contributed to the decline or was just a marker for a more aggressive course of Alzheimer’s.

“I don’t believe that seizures cause Alzheimer’s or that treating seizures will cure Alzheimer’s,” said Cole. “I think there’s a hypothesis that the seizures contribute to the [Alzheimer’s] disease burden.”

Watch our video about links between Alzheimer’s and epilepsy.

Tau: Agent or bystander?

Tangles of an abnormal form of tau protein are characteristic of Alzheimer’s brain tissue, as well as chronic traumatic encephalopathy. Now there’s evidence that tau may be associated with some cases of epilepsy, too.

Tau is a key protein that’s normally involved in the cytoskeleton—a complex network in the cytoplasm that helps manage many functions, including maintaining a cell’s shape and the process of cell division. In humans, tau is found mainly in neurons, and helps to stabilize axon microtubules.

Tau has more than 70 sites that can potentially hold a phosphate group (PO4). Partial phosphorylation is par for the course, but a fully phosphorylated tau protein (p-tau) detaches from microtubules and congregates in the cell, clinging to other p-taus and forming tangles that are associated with neuronal damage and cell death.

In a study of 33 people with temporal lobe epilepsy (TLE) who underwent epilepsy surgery, researchers analyzed the resected tissue and gave it a p-tau burden score. Higher burden scores predicted cognitive decline in the year after surgery and were associated with the presence of secondary generalized seizures before surgery. The researchers did not find levels of amyloid-beta, another key protein associated with Alzheimer’s disease. They suggest that any underlying tau-related neurodegeneration in people with TLE is not a typical Alzheimer’s disease process, but that perhaps certain types of epilepsy have a unique tau deposition pattern.

A 2011 post-mortem study of people with epilepsy found either mild or moderate Alzheimer’s disease tau pathology in almost 70% of them, with a particular association in those who had a history of traumatic brain injury. Tau burden was significantly associated with progressive cognitive decline. Focal epilepsy was more often associated with higher tau burdens, compared with genetic or idiopathic generalized epilepsy.

Could targeting tau reduce seizures?

Terence O'Brien
Terence O'Brien

Given the potential links between tau and epilepsy—particularly epilepsy acquired after a brain insult—targeting the tau protein could be an opportunity to develop a true anti-epileptogenic treatment, said Terence O’Brien, program director for Alfred Brain and director of neurology at The Alfred Hospital, Melbourne. Animal models suggest this possibility. Genetically modified mice that overexpress human p-tau have spontaneous seizures, while tau knockout mice—which lack tau, and therefore cannot generate p-tau—are protected from seizures, both in genetic epilepsy models and in chemically induced seizure models.

The enzyme family called protein phosphatase 2A (PP2A) is involved in multiple types of phosphorylation and dephosphorylation within cells. There are more than 90 variants of PP2A. One, called PP2A/Bα, is considered to be the primary tau phosphatase. A decrease in its activity correlates with increased tau phosphorylation in vivo and in Alzheimer’s disease.

A study of three rat models of epileptogenesis found that each model showed a decrease in PP2A activity and an increase in p-tau in the epileptogenic brain regions. Treatment with sodium selenate — a known activator of the PP2A enzyme family — reduced the levels of p-tau and mitigated epileptogenesis.

Studies using animal models of traumatic brain injury show similar results: Treatment with sodium selenate increases PP2A levels, decreases p-tau, attenuates brain damage and improves behavioral outcomes.

“If you can decrease tau phosphorylation, you decrease seizures,” said O’Brien.

Sodium selenate also has been found to be protective in mouse models of Alzheimer’s disease, in which it activates PP2A, decreases p-tau and reverses memory deficits.

Abnormal phosphorylation of tau causes microtubule depolymerization and the formation of insoluble cytoplasmic p-tau, which aggregate and assemble to form neurofibrillary tangles (NFTs)
Abnormal phosphorylation of tau causes microtubule depolymerization and the formation of insoluble cytoplasmic p-tau, which aggregate and assemble to form neurofibrillary tangles (NFTs). From Zheng et al., Mol Neurobiology 2014.