ReviewShared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms
Highlights
► Remarkably, Alzheimer’s disease (AD) and epilepsy have some common characteristics. ► Similarities also exist in animal models of the two diseases. ► Psychiatric symptoms of AD share some characteristics of comorbidities in epilepsy. ► Overlapping mechanisms have been suggested for some aspects of AD and epilepsy.
Introduction
Disorders or conditions that affect synaptic function are often associated with seizures or are risk factors for epilepsy, including traumatic brain injury, autism, schizophrenia, and Alzheimer's disease (AD). This is not surprising, considering that the brain is made up of over 1 billion neurons, and each neuron can form tens of thousands of synapses. Such a complex structure requires numerous cellular and circuit mechanisms to regulate neuronal network activity and maintain stable function that also can adapt to environmental demand [1]. Although the brain can generally meet this challenge, disorders that impact synaptic function may overcome the capacity to maintain normal function. Changes to synaptic function may result in seizures by numerous mechanisms, creating an imbalance between excitation and inhibition either directly or indirectly, e.g., by inducing maladaptive compensatory responses.
Focusing on synaptic regulation is important in AD, which has been referred to as a “disease of synaptic failure” [2], [3]. It also is considered to be central in epilepsy, and therefore, it may not be surprising that seizures have been described in patients with AD [4], [5], [6], [7]. The fact that patients with AD have recurrent spontaneous seizures, which defines ‘epilepsy,’ has also been noted [6], [8], but the role of epilepsy in AD pathophysiology has largely been unexplored. Seizures have traditionally been attributed to neuronal loss in the late stages of disease, and may, therefore, be a possible epiphenomenon of little pathophysiological relevance. However, as discussed in this review, recent studies have provided more experimental support for the idea that there is a greater connection between epilepsy and AD than previously recognized. These experimental studies, particularly those utilizing mouse models of AD, support the idea that seizures may contribute in a critical fashion to the emergence of AD symptoms, i.e., cognitive impairment, in early stages of AD [9]. Notably, epilepsy and AD also have similar psychiatric co-morbidities, suggesting that seizures may influence a wider range of brain function in AD than memory impairment. This article reviews the evidence that cognitive and psychiatric symptoms of AD and TLE are not merely byproducts of widespread temporal lobe pathology in both conditions but may share underlying mechanisms.
Section snippets
Seizures in patients with AD
The occurrence of seizures in patients with AD has been thoroughly reviewed recently [4], [5], [6], [7]. The incidence of unprovoked seizures is 5–10-fold greater in sporadic AD than in reference populations, and as much as 87-fold greater in patients with “early” disease onset (before 60 yrs of age [5], [6], [10], [11], [12]). In autosomal dominant forms of AD, the relationship between seizures and AD is most remarkable. In these forms of AD, there are either mutations in amyloid precursor
Cognitive and behavioral impairments in patients with AD and TLE
One of the reasons that the idea of seizures in AD has gained so much interest is that TLE and AD can appear quite similar in their cognitive and behavioral impairments. These impairments are considered “co-morbidities” in TLE and include deficits that span multiple cognitive domains and a wide range of ‘emotional’ symptoms ranging from mood disorders such as depression to anxiety. Clinically, AD is characterized by a progressive loss of cognitive function, particularly regarding episodic
Psychiatric symptoms in patients with AD and TLE or epilepsy
Changes in behavior are common in both epilepsy and in AD [94], [95], [96]. Almost all people (over 90%) diagnosed with AD develop neuropsychiatric symptoms at some stage during disease progression [94], [95], [96], typically at early stages. Indeed, regression analyses indicate that in patients with AD, there are significant associations between mood disorders [97]. Similarly, depression, anxiety, and other neuropsychiatric symptoms are common in people with epilepsy [94], [95], [98].
That such
Conclusions and avenues for future research
Identifying similarities and differences between epilepsy and AD is important because it could help define new targets for drug development in these diseases. Broadening the target pool is greatly needed in epilepsy because the antiepileptic drugs that are currently available often fail to stop seizures or have adverse side effects. In AD, new drugs are also sorely needed, because disease-modifying therapeutics are currently not available, and the numbers of affected individuals are growing
Acknowledgments
JC is grateful for support from the Alzheimer's Association and the Margaret Q. Landenberger Research Foundation. HS acknowledges support from NIH, the Alzheimer's Association, and the New York State Office of Mental Health.
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2021, Biomedicine and PharmacotherapyAltered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice
2021, Neurobiology of DiseaseCitation Excerpt :These data suggest that abnormal neuronal activity may contribute directly to development of AD neuropathology including Aβ accumulation. The extent to which these abnormal brain electrical discharges may drive cognitive decline directly (Chin and Scharfman, 2013; Lam et al., 2017) or indirectly through interactions with AD neuropathology is currently unknown. Findings of abnormal hyperexcitability and seizures have been replicated in several mouse models of AD (Gureviciene et al., 2019; Gurevicius et al., 2013; Minkeviciene et al., 2009; Palop et al., 2007; Roberson et al., 2011; Ziyatdinova et al., 2016) including data from our own group showing that even a single, mild pharmacologically-induced seizure following a low dose of kainic acid can lead to memory deficits in young APP/PSEN1 mice (Mi et al., 2018).