AD is the most common cause of dementia. Currently, 30 million people worldwide suffer from Alzheimer's dementia and the World Health organization projects that this number will triple over the next 20 years.1 The cumulative incidence of Alzheimer dementia has been estimated to rise from about 5% by age 70 to 50% by age 90, making it a very common disease.2 Increasing longevity and demographic shifts in many societies will stress the health systems unless a cure for AD is found—or at least any therapy that postpones the onset of the dementia by 5 to 10 years for the time being. AD is a polygenetic neurodegenerative brain disorder characterized by neocortical atrophy developing over decades, showing the increasing loss of synapses and neurons first described by Alois Alzheimer in 1907.3 Variations in the genes encoding the amyloid precursor proteins, presenilin-1 and presenilin-2, can directly cause Alzheimer's disease. The patients often display an early onset of dementia in their forties, and these deterministic genes affect whole families and patients with trisomy 21. They, however, account for only 1% of all cases of AD. The remaining 99% of sporadic AD occurs predominantly in patients older than 65 years;4 These patients also inherit 60% to 80% of their risk for late-onset AD, although it is not connected to the aforementioned genes, with the remainder being environmental.4,5 In late-onset AD many different genes—some still unidentified—are involved, each only attributing a minor fraction of the individual's overall risk, making it a possible example of antagonistic pleiotropy.6 Recently, several genome-wide association studies have identified new candidates (for reviews and databases see http://www.alzgene.org). The best characterized genetic risk factor in late-onset AD is the apolipoprotein E4 (ApoE4) genotype with ApoE4 carriers having a 4- to 10-fold increased odds ratio of developing AD.7 The ApoE4 allele is an ancestral variant. The human ApoE2 and ApoE3 alleles are fairly recent mutations—less than 200 000 years old.8 ApoE3 is the most frequent allele, with frequencies of about 60% in human populations. In contrast, ApoE4 has a frequency of about 10%. This implies that ApoE3 and ApoE2 must possess an advantage in order to have gained prevalence in human populations so quickly; clinical and preclinical data point to higher synaptic plasticity and repair capacities in carriers of ApoE2 and ApoE3, which may explain the selection bias.9 The consumption and adaption of humans to a diet rich in meat and animal fats can also be a reason for the selection of ApoE3.10The neuropathological hallmarks of the atrophy process in AD are the presence of senile plaques (amyloid deposits) and neurofibrillary tangles in autopsied brains.11 Neurofibrillary tangles are composed of hyperphosphorylated tau protein located within neurons, whereas senile plaques are made up largely of amyloid-P species aggregating in the extracellular space. These neuropathological changes start in the entorhinal cortex and hippocampal formations, later spreading into other temporal, parietal, and finally frontal association cortices.12-14 The first lesions characteristic of AD appear in poorly myelinated limbic neurons in system areas related to memory and learning, such as the hippocampus and the association cortex. Highly myelinated neurons are only affected in the final phases of the disease.15 Low myelinization increases the overall energy expenditure of neurons. In addition, subcortical neuron loss occurs in the nucleus basalis of Meynert and the locus ceruleus, impairing the cholinergic and noradrenergic transmitter systems in the neocortex.16,17 The parietal lobe, along with certain areas of the prefrontal lobe, is one of the last areas of the human brain to myelinate, and many of its neurons remain poorly myelinated for the entire lifespan, which may explain their vulnerability to factors capable of triggering AD.18-20 The atrophy runs slowly, but while in healthy aging only 0.2% to 0.41% of the brain volume vanishes per year, the rates in AD may be ten times that, and in especially vulnerable regions like the hippocampal formation atrophy rates might be even more devastatingly high and surpass 10% per year (see also Figure 1).21-23 In terms of neuropsychological tests, regional atrophy, and glucose metabolism correlate well with test results.24,25 Left hippocampal gray matter volume, for example, significantly correlates with performance in memory tasks, and left temporal gray-matter volume is related to performance in language tasks. The rate of change in the left hippocampus correlates with decline of performance in the Boston Naming Test Mini-Mental Status Examination, and the trailmaking test B.24 Such analyses help with the definition of special AD subtypes like posterior cortical atrophy, or the logopenic variant of AD.