**1. Introduction**

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive loss of memory, orientation, sanity, and language. AD is a slow evolving disorder of multigenic nature with an average duration between 8 and 12 years. During the disease onset, symp‐ toms are overlooked generally for the first 2 or 3 years. There are few hereditary cases (genetic or familial AD) resulting from autosomal dominant inheritance of chromosomal alterations. This condition is the most common type of dementia, and it is globally recognized as one of the leading causes of morbidity and mortality among the advanced age population. In 2004, approximately 44 million cases of dementia were diagnosed worldwide and the number of cases in 2050 is estimated to be 135 million [1].

In AD, there is neuron loss and two typical alterations appear: the neuritic plaque produced by the β-amyloid (Aβ) and the neurofibrillary tangle that contains the hyperphosphorylated Tau protein as the main component.

Neuritic plaques are sphere-like structures in which the major component is the β-amyloid (Aβ) protein. The latter is generated by proteolytic cleavage of a larger protein, βAPP (Aβ precursor protein), and the neurofibrillar tangle, an intracellular damage affecting pyramidal neurons [2].

When the disease is diagnosed, its pathology has progressed several years [3]. Cerebral changes underlying AD probably develop 20–30 years before the first symptoms appear.

AD diagnosis combines psychological and imaging tests as well as the exclusion of neurologic disorders [4].

The pathological processes frequently linked to AD are as follows: aging, amyloid deposition, neurofibrillar degeneration, synaptic loss, inflammation, loss of vascular integrity, and neuron loss [5].

The development of tangles and plaques leads to neuron death. Tangles are mainly located at the entorhinal cortex, hippocampus, parahippocampal gyrus, amygdala, and frontal, tempo‐ ral, parietal, and occipital cortices and some subcortical nuclei projected toward these regions [6].

Tangles are composed by paired helical filaments (PHF), in which the latter are gathered in helixes. Neuritic plaques are microscopic foci of extracellular amyloid depositions associated with axon and neurite damage. They are found in large amounts at the limbic and association cortex [7].

At the neuritic plaques, it is observed an abnormal extracellular accumulation of the Aβ peptide, comprised by 40 or 42 amino acids (Aβ40 and Aβ42) [8]. Dystrophic neurites are located both within and surrounding the amyloid depositions, and they are distinguished by structural abnormalities including lysosomes, mitochondria, and PHF.

These plaques are associated with microglia either contiguous or within the amyloid nucleus. The period of time for neuritic plaque development is unknown. Most of the fibrillar Aβ located at the neuritic plaques is the species ending in the amino acid 42 (Aβ42), which is the slightly larger and hydrophobic form, prone to aggregation [9].

In AD, there is neurotransmitter deficiency at brain level. Dementia symptoms develop because the severe degeneration suffered by neurons that synthesize and liberate acetylcho‐ line. The level and activities of the synthesizing and degrading enzymes, choline acetyltrans‐ ferase and acetylcholinesterase, decrease at the limbic and cerebral cortex showing an associated loss of cholinergic cell bodies at the septal nucleus and the anterior forebrain cholinergic system [6].

Glutamatergic system is also deteriorated in AD. There are interactions between β-amyloid and glutamate at the synaptic function: the former has influence on the generation of the latter and glutamate levels may be modified by the peptide. Concentration changes of these two molecules may impact AD progression. Because hippocampus and cortex are fundamental for learning and memory, it is possible that glutamatergic neuron degeneration appears at early stages of AD [10].

The cerebral regions severely affected by AD are as follows: hippocampus, entorhinal cortex, amygdala, cerebral cortex, and some subcortical areas such as cholinergic neurons at the anterior forebrain, serotoninergic neurons at the dorsal raphe, and noradrenergic neurons at the locus coeruleus [11].

Four main genes have been associated to Alzheimer's disease; all of them are processed by ribonucleic acid (RNA) alternative splicing.
