Many mutations in the presenilin-1 gene are associated with epilepsy. Trisomy-21 patients with early-onset AD also have frank seizures in 84% of cases. Many patients with AD show fluctuations in cognitive functions such as transient episodes of amnestic wandering or disorientation. While an intermittent inability to retrieve memories cannot be easily explained by relatively protracted processes such as neuronal loss, plaque deposition, or tangle formation, an abnormal epileptic activity of neuronal networks can. Extensive work in this field was published by the group of Lennart Mucke. They see the possibility that high levels of β-amyloid induce epileptiform activity, which triggers compensatory inhibitory responses to counteract overexcitation that lead to changes in synaptic circuitry and an increase in inhibitory activity in, eg, the temporal cortex. This leads to changes in the texture of the neural networks involved and might explain disruptions of the networks as seen in the default mode network (DMN) in AD.58-60 Transynaptic progression of toxicity effects of β-amyloid inducing epileptic activity from the entorhinal cortex to other brain regions may explain cognitive dysfunctions in AD.61AD affects the default mode network (DMN). This network comprises brain regions that are active and interconnected in a wakeful state when the mind is not focused on something specific. Anatomically it includes part of the medial temporal lobe, the medial prefrontal cortex, the posterior cingulate cortex, ventral precuneus, and the medial, lateral, and inferior parietal cortex. This networks develops during childhood and adolescence and reaches full integration in adults, characterized by coherent infraslow EEG oscillations smaller than 0.1 Hz. The DMN is linked to other low-frequency resting state networks in the brain and is anti-correlated with the ventral and dorsal attention network. Measurements of glucose metabolism with positron emission tomography (PET), of structural atrophy with MRI, and intrinsic and task-evoked brain activity with fMRI in AD all suggest an increasing disruption in the DMN.62When AD patients undergo a FDG-PET the pattern of hypometabolism often mirrors the same regions that belong to the posterior parts of the DMN, namely the posterior cingulate cortex, the retrosplenial cortex, inferior parietal lobule, and the lateral temporal cortex.63 Such hypometabolism correlates with the mental status while AD progresses.64 Probands with a genetic risk for AD of being homozygous for ApoE4 develop this hypometabolism already quite early in the course of the disease.62,65 Disruption in the DMN at the preclinical stages of the disease by accelerated cortical atrophy affects the medial temporal lobe and the posterior cingulum and the retrosplenial cortex.63,66 Also, analysis of task-induced deactivation and analysis of intrinsic activity correlations show an impaired DMN consistent with metabolic and structural changes.67-69 The DMN is coupled with hippocampus during memory retrieval but not during memory encoding, pointing to the special positioning of the hippocampus between short-term and long-term memory.70 Encoding structures of the DMN are among the first to show accumulation of β-amyloid even before symptoms emerge and images of β-amyloid plaques taken at the earliest stages of AD show a distribution that is remarkably similar to the anatomy of the default network.71 Buckner et al speculate that AD pathology forms preferentially throughout the DMN and may be linked to DMN activity.63 Their basic idea is that the DMN's continuous activity augments an activity-dependent or metabolism-dependent cascade that starts the β-amyloid cascade in these brain regions. Hence, memory would be affected preferentially by the disease because the DMN is mainly relying on cortical structures that are also vital to memory functions and “burns” them during activity. Interestingly, ApoE4 carriers have also been found to have a higher rate of activity in the DMN at rest compared with ApoE2 or ApoE3 carriers, and decreased connectivity.