Patients with subjective memory impairment also already showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe using (fludeoxyglucose positron emission tomography, FDG-PET). Their gray matter volume was reduced in the right hippocampus. At follow-up, these patients showed poorer performance on measures of episodic memory. The observed memory decline was associated with reduced glucose metabolism in the right precuneus at baseline. The authors conclude that their concept of subjective memory impairment may define the earliest clinical manifestation of AD.53 In another study patients with subjective memory underwent an associative episodic memory task matching faces to professions, including encoding, recall, and recognition, and a working memory task during functional magnetic resonance imaging (f'MRI). They showed a reduction in right hippocampal activation during episodic memory recall, still in the absence of performance deficits. This was accompanied by increased activation of the right dorsolateral prefrontal cortex. No such differences in performance and brain activation were detected for working memory. This may indicate subtle early neuronal dysfunction on the hippocampal level and compensatory mechanisms that preserve memory performance.54Regarding ApoE4, cognitively unimpaired young elderly with and without subjective memory impairment were tested on episodic memory and on tasks of speed and executive function. Medial temporal lobe volumetric measures were calculated from MRI images. In the subjective memory impairment group, ApoE4 carriers performed worse on the episodic memory and showed smaller left hippocampal volumes. In the individuals without memory complaints, the ApoE4 carriers performed better on episodic memory and had larger right hippocampal volumes (P=0.039). The interaction of group and ApoE genotype was significant for episodic memory and right and left hippocampal volumes. The negative effect of ApoE4 on episodic memory and hippocampal volume in the group suffering from subjective memory decline also supports the notion that this may be a prodromal condition of AD.55 In conclusion, the mere subjective feeling of being cognitively altered compared with the individual's reference past can already be accompanied by subtle brain changes that if ongoing may herald increasing memory decline in the future.Impaired sense of smell or hyposmia is one of the earliest clinical features in neurodegenerative disorders like both AD or Parkinson's disease.56 This has been known for decades and relates well to the finding that, for example, plaque formation in AD starts in the entorhinal cortex, the region also responsible for processing of information on smell. A recent meta-analysis of 81 studies indicated that AD and PD patients are more impaired on odor identification and recognition tasks than on odor detection threshold tasks. AD patients were found to be more impaired on higher-order olfactory tasks involving specific cognitive processes.57 Odor identification and recognition tests can be easily implemented in cognitive test batteries to detect already subclinical cases of AD. The impairment of smell recognition is of clinical importance, as patients often report malodorous sensations and changes in, eg, the taste of foods leading to behavioral alterations. Consequences may range from increasing malnutriton to the development of delusions of poisoning that may trigger aggressive behavior. The deterioration of the neural network in the entorhinal cortex leads to an impairment in the ability to store and retrieve different representations of smell, with the decaying network yielding increasingly “default values” that have the tendency to be of rather unpleasant character. This feature of the neural network of smell memory reflects the evolutionary pressure towards the secure recognition of “bad” smells pointing to poisonous or rotten food that is pivotal for the survival of the organism.The incidence of unprovoked seizures is clearly higher in sporadic AD than in reference populations with implications for memory functions. Nonconvulsive epileptiform activity could underlie at least some of the cognitive impairments observed in AD. Up to 1 in 5 patients with sporadic AD has at least 1 unprovoked clinically apparent seizure during their illness, and clinical guidelines recommend obligatory treatment for this condition. The risk of epileptic activity is greater in early-onset AD.