2.1 Macroscopic Alzheimer's disease (AD) is characterized by a global involvement, bilateral and symmetrical in both hemispheres with cortical predominance. There is reduced transparency and fibrosis of the leptomeninges and subarachnoid large gaps remains in the spaces left between the cerebral sulci. When the meninges are removed we can see a pale brain with weight decrease of approximately 800 to 1000g from 1300 to 1700g in the normal adult. There is greater involvement of the association areas (fronto temporal and parietal) and to a lesser degree of primary motor and sensory areas. The most affected region is the mesial temporal lobe and especially the entorhinal cortex. The increase of the ventricles is secondary to parenchymal loss. A recent neuroimage-based quantitative meta-analysis revealed that early AD affects structurally the hippocampal regions (figures 1.A and 1.B), while functionally affects the inferior parietal lobules (figures 1.C and 1.D), which might be www.intechopen.com Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets www.intechopen.com Alzheimer´s Disease-The New Actors of an Old Drama 5 2.2 Microscopic Corroborate the findings described above. It were also observed important changes such as subcortical neuronal depopulation of the nucleus basalis of Meynert, raphe nuclei, the nucleus ceruleus, amygdala, and white matter lesions. The two typical lesions that define AD are senile plaques and neurofibrillary tangles: 2.2.1 Senile Plaques (SP) Observed in the interstice, between neurons. They measure between 20 and 100 microns and consist of a core which principal component is beta amyloid (A). This core is surrounded by a nest formed by degenerating neurites, activated microglia and astrocytes. Other substances that conform the SP are the alpha-synuclein (principal not amyloid component), alpha 1 antichymotrypsin, alpha 2 macroglobulin, apolipoprotein E, ubiquitin and the presenilins. Degenerative neurons are also distinguished around but not in contact with the plaques. According his appearance they are classified as: a. Difuse. Formed by a delicate network of fine filaments of amyloid fibrils without degenerate neurites. Center and its boundaries are not well defined. b. Primitive. Are the most common. They are characterized by disordered extracellular A deposits wich are poorly or not fibrillar. Center is not well defined but the borders are more accurate. c. Classic. Also called neuritic plaques, amyloid have a center surrounded by a crown composed of reactive astrocytes, microglia and dystrophic neurites corresponding to dendrites and degenerate axons. d. Burns. Present only a condensed central amyloid. It has no cellular components. These forms represent different developmental stages of the plaques, beginning with the accumulation of diffuse amyloid, then it is organized and defined, by associating the immune response. Finally, the cellular elements disappear. The SP are relatively rare in limbic structures and neocortex and are more visible ...