Seizures are characterized by periods of high neuronal activity and are caused by alterations in synaptic function that disrupt the equilibrium between excitation and inhibition in neurons. While often associated with epilepsy, seizures can also occur after brain injuries and interestingly, are common in Alzheimer’s patients. While Alzheimer’s patients rarely show the common physical signs of seizures, recent research has shown that electroencephalogram (EEG) technology can detect nonconvulsive seizures in Alzheimer’s patients. Furthermore, patients with Alzheimer’s have a 6- to 10-fold increase in the probability of developing seizures during the course of their disease compared to healthy controls.2 While previous research has focused on the underlying molecular mechanisms of Aβ tangles in the brain, the research presented here relates seizures to the cognitive decline in Alzheimer’s patients in an attempt to find therapeutic approaches that tackle both epilepsy and Alzheimer’s.
The hippocampus is found in the temporal lobe and is involved in the creation and consolidation of new memories. It is the first part of the brain to undergo neurodegeneration in Alzheimer’s disease, and as such, the disease is characterized by memory loss. Alzheimer’s is different than other types of dementia because patients’ episodic memories are affected strongly and quickly. Likewise, patients who suffer from epilepsy also exhibit neurodegeneration in their hippocampi and have impaired episodic memories. Such similarities led researchers to hypothesize that the two diseases have the same pathophysiological mechanisms. In one study, four epileptic patients exhibited progressive memory loss that clinically resembled Alzheimer’s disease.6 In another study, researchers found that seizures precede cognitive symptoms in late-onset Alzheimer’s disease.7 This led researchers to hypothesize that a high incidence of seizures increases the rate of cognitive decline in Alzheimer’s patients. However, much is yet to be discovered about the molecular mechanisms underlying seizure activity and cognitive impairments.
Amyloid precursor protein (APP) is the precursor molecule to Aβ, the polypeptide that makes up the Aβ plaques found in the brains of Alzheimer’s patients. In many Alzheimer’s labs, the J20 APP mouse model of disease is used to simulate human Alzheimer’s. These mice overexpress the human form of APP, develop amyloid plaques, and have severe deficits in learning and memory. The mice also have high levels of epileptiform activity and exhibit spontaneous seizures that are characteristic of epilepsy.11 Understanding the long-lasting effects of these seizures is important in designing therapies for a disease that is affected by recurrent seizures. Thus, comparing the APP mouse model of disease with the temporal lobe epilepsy (TLE) mouse model is essential in unraveling the mysteries of seizures and cognitive decline.
Shared Pathology of the Two Diseases
The molecular mechanisms behind the two diseases are still unknown and under much research. An early observation in both TLE and Alzheimer’s involved a decrease in calbindin-28DK, a calcium buffering protein, in the hippocampus.10 Neuronal calcium buffering and calcium homeostasis are well-known to be involved in learning and memory. Calcium channels are involved in synaptic transmission, and a high calcium ion influx often results in altered neuronal excitability and calcium signaling. Calbindin acts as a buffer for binding free Ca2+ and is thus critical to calcium homeostasis.
Some APP mice have severe seizures and an extremely high loss of calbindin, while other APP mice exhibit no loss in calbindin. The reasons behind this is unclear, but like patients, mice are also very variable.
The loss of calbindin in both Alzheimer’s and TLE is highly correlated with cognitive deficits. However, the molecular mechanism behind the calbindin loss is unclear. Many researchers are now working to uncover this mechanism in the hopes of preventing the calbindin loss, thereby improving therapeutic avenues for Alzheimer’s and epilepsy patients.
Seizures and Neurogenesis
The dentate gyrus is one of the two areas of the adult brain that exhibit neurogenesis.13 Understanding neurogenesis in the hippocampus can lead to promising therapeutic targets in the form of neuronal replacement therapy. Preliminary research in Alzheimer’s and TLE has shown changes in neurogenesis over the course of the disease.14 However, whether neurogenesis is increased or decreased remains a controversial topic, as studies frequently contradict each other.
Many researchers study neurogenesis in the context of different diseases. In memory research, neurogenesis is thought to be involved in both memory formation and memory consolidation.12 Alzheimer’s leads to the gradual decrease in the generation of neural progenitors, the stem cells that can differentiate to create a variety of different neuronal and glial cell types.8 Further studies have shown that the neural stem cell pool undergoes accelerated depletion due to seizure activity.15 Initially, heightened neuronal activity stimulates neural progenitors to divide rapidly at a much faster rate than controls. This rapid division depletes the limited stem cell pool prematurely. Interestingly enough, this enhanced neurogenesis is detected long before other AD-linked pathologies. When the APP mice become older, the stem cell pool is depleted to a point where neurogenesis occurs much slower compared to controls.9 This is thought to represent memory deficits, in that the APP mice can no longer consolidate new memories as effectively. The same phenomenon occurs in mice with TLE.
The discovery of this premature neurogenesis in Alzheimer’s disease has many therapeutic benefits. For one, enhanced neurogenesis can be used as a marker for Alzheimer’s long before any symptoms are present. Furthermore, targeting increased neurogenesis holds potential as a therapeutic avenue, leading to better remedies for preventing the pathological effects of recurrent seizures in Alzheimer’s disease.
Research linking epilepsy with other neurodegenerative disorders is still in its infancy, and leaves many researchers skeptical about the potential to create a single therapy for multiple conditions. Previous EEG studies recorded Alzheimer’s patients for a few hours at a time and found limited epileptiform activity; enhanced overnight technology has shown that about half of Alzheimer’s patients have epileptiform activity in a 24-hour period, with most activity occurring during sleep1. Recording patients for even longer periods of time will likely raise this percentage. Further research is being conducted to show the importance of seizures in enhancing cognitive deficits and understanding Alzheimer’s disease, and could lead to amazing therapeutic advances in the future.
- Vossel, K. A. et. al. Incidence and Impact of Subclinical Epileptiform Activity. Ann Neurol. 2016.
- Pandis, D. Scarmeas, N. Seizures in Alzheimer Disease: Clinical and Epidemiological Data. Epilepsy Curr. 2012. 12(5), 184-187.
- Chin, J. Scharfman, H. Shared cognitive and behavioral impairments in epilepsy and Alzheimer’s disease and potential underlying mechanisms. Epilepsy & Behavior. 2013. 26, 343-351.
- Carter, D. S. et. al. Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus. Epilepsy Res. 2008. 79(2-3), 213-223.
- Jin, K. et. al. Increased hippocampal neurogenesis in Alzheimer’s Disease. Proc Natl Acad Sci. 2004. 101(1), 343-347.
- Ito, M., Echizenya, N., Nemoto, D., & Kase, M. (2009). A case series of epilepsy-derived memory impairment resembling Alzheimer disease. Alzheimer Disease and Associated Disorders, 23(4), 406–409.
- Picco, A., Archetti, S., Ferrara, M., Arnaldi, D., Piccini, A., Serrati, C., … Nobili, F. (2011). Seizures can precede cognitive symptoms in late-onset Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD, 27(4), 737–742.
- Zeng, Q., Zheng, M., Zhang, T., & He, G. (2016). Hippocampal neurogenesis in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Neuroscience, 314, 64–74. https://doi.org/10.1016/j.neuroscience.2015.11.05
- Lopez-Toledano, M. A., Ali Faghihi, M., Patel, N. S., & Wahlestedt, C. (2010). Adult neurogenesis: a potential tool for early diagnosis in Alzheimer’s disease? Journal of Alzheimer’s Disease: JAD, 20(2), 395–408. https://doi.org/10.3233/JAD-2010-1388
- Palop, J. J., Jones, B., Kekonius, L., Chin, J., Yu, G.-Q., Raber, J., … Mucke, L. (2003). Neuronal depletion of calcium-dependent proteins in the dentate gyrus istightly linked to Alzheimer’s disease-related cognitive deficits. Proceedings of the National Academy of Sciences of the United States of America, 100(16), 9572–9577. https://doi.org/10.1073/pnas.1133381100
- Research Models: J20. AlzForum: Networking for a Cure.
- Kitamura, T. Inokuchi, K. (2014). Role of adult neurogenesis in hippocampal-cortical memory consolidation. Molecular Brain 7:13. 10.1186/1756-6606-7-13.
- Piatti, V. Ewell, L. Leutgeb, J. Neurogenesis in the dentate gyrus: carrying the message or dictating the tone. Frontiers in Neuroscience 7:50. doi: 10.3389/fnins.2013.00050
- Noebels, J. (2011). A Perfect Storm: Converging Paths of Epilepsy and Alzheimer’s Dementia Intersect in the Hippocampal Formation. Epilepsia 52, 39-46. doi: 10.1111/j.1528-1167.2010.02909.x
- Jasper, H.; et.al. In Jasper’s Basic Mechanisms of the Epilepsies, 4; Rogawski, M., et al., Eds.; Oxford University Press: USA, 2012