New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Soluble forms of tau are toxic in Alzheimer's disease

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies

Epilepsy; Antiepileptic Drug Profiles

Twenty antiepileptic drugs (AEDs) are available in the USA and many areas of the world for chronic therapy to prevent or minimize seizures. For some seizure types, efficacy differences are modest, but all the drugs are distinctive in one or more ways and possess unique mechanisms of action, side effects, or pharmacokinetics. An understanding of these properties is needed to make an optimal selection of monotherapy and combined AED therapy

Epilepsy; Drug Treatment Principles

Antiepileptic drug selection is most dictated by the expectation that the drug will control or maximally prevent seizures. Evidence-based studies confirm that some drugs are superior for certain seizure types such as absence and myoclonic. Differences in efficacy for partial onset seizures are often modest, so the choice of drug may be decided by other factors such as expected adverse effects, comorbidities, pharmacokinetics, age, gender, and cost. No drug of choice exists for each seizure type. Rather careful individualized selection is indicated

Epilepsy Treatment Strategies

Factors in everyday life can alter the probability of seizure occurrence. These include missed medication, emotional stress, sleep deprivation, excessive alcohol use, and hormonal influences. The majority of these factors can be modified or regulated to decrease the likelihood of frequent seizures in addition to the use of antiepileptic drugs