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 Inhibitors,research,lifescience,medical neurons are only affected in the final phases of the

disease.15 Low myelinization increases the overall energy expenditure Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical 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 Inhibitors,research,lifescience,medical 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 ARQ 197 order decline of performance RepSox order 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.24-31 On the molecular level we find a downregulation of synaptic genes across multiple brain regions and widespread proteomic signs of synaptic stress or decay in the cerebrospinal fluid (CSF) or blood.32-34 Changes in the molecular fine structure of AD brains also arise independently of atrophy as resonance spectroscopic investigations in AD imply.35 Figure 1.