Role of Seizures in the Pathophysiology of Down Syndrome and Alzheimer’s Disease

The most common genetic cause of intellectual disability is Down syndrome (DS). Alzheimer’s disease (AD), characterized pathologically by neuritic plaques composed of Aβ amyloid protein and neurofibrillary tangles made up of τ protein, represents the prototype senile onset dementia. A significant proportion of DS patients develop AD in later life with risk factors described for those particularly predisposed. Seizure disorders are described in both, with diverse as well as common underlying pathogenic mechanism, that have significant clinical and therapeutic implications.

In DS, seizures are seen mainly in infancy and beyond 40 years. Overall, the predominant seizure types are infantile spasm, generalized tonic clonic (GTCS), and focal. In the older age group, a specific seizure type called late-onset myoclonic epilepsy (LOMEDS) is seen, which clinically simulates a progressive myoclonic epilepsy phenotype. Various mechanisms, like abnormal shape of the brain, impaired membrane excitability, altered neurotransmitter circuitry, and overexpression of genes because of a triplicate 21st chromosome, contribute to the causation of seizure in DS. Moreover, with advancing age, AD-like changes in the brain also contribute to the pathogenesis of LOMEDS.

There is increased risk of seizures in AD compared to age-matched healthy individuals. The commonest seizure types are focal and generalized and occasionally myoclonic. Underlying pathogenic mechanisms include formation of Aβ plaques and neurofibrillary tangles, selective hippocampal injury, neurotransmitter imbalance, and channelopathies. Studies have shown that temporal lobe epilepsy and AD have similarities in pathology as well as clinical implications.

In both these disorders, seizures play an important role in pathophysiology and clinical manifestations. Early recognition and appropriate diagnosis and management are imperative as this has significant treatment and overall outcome related implications.

Keywords: Alzheimer’s disease, clinical implications, Down syndrome, pathophysiology, seizure.