More than a century ago, a German doctor called Alois Alzheimer (1864-1915) discovered lesions in the brain of a patient that had never been observed before. In a 1907 publication he reported a case of impaired brain function that caused dementia [7] . The problem had to do with atrophied neurons in different parts of the brain, which was full of plaques and fibers twisted into one another. Since then, deposits of this kind have come to be called senile plaques and neurofibrillary tangles, and are tell-tale signs of Alzheimer’s disease [8] . These plaques have a toxic effect on neurons, causing their death [9] . With neuronal death comes dementia―the progressive impairment of cognitive function, mainly affecting memory, thinking, and concentration. When the symptoms worsen, other brain functions are also affected, like movement [10] . Amyloid plaques, present in people with AD, are formed by the build-up of beta-amyloid peptide [11] , which aggregates to form amyloid plaques that are deposited on the outside of neurons [9] . Neurofibrillary tangles, also a feature of the disease, are formed when tau proteins accumulate in the neuronal cytoplasm [12] . This protein is involved in the stabilization of microtubules in the neuronal cytoskeleton. In AD, the tau proteins are structurally altered and form neurofibrillary tangles [13] , which are deposited inside neurons and cause neuronal death (Figure 3).

It has been shown that the beta-amyloid plaques attached to the outside of neurons affect the activity of kinase enzymes, which consequently add an excessive quantity of phosphate to the tau protein, triggering alterations in it and the formation of fibrillary tangles and their build-up inside neurons [7] [15] . These tangles are toxic and cause neuronal death. When this occurs, acetylcholine neurotransmitter levels fall, impairing cognitive function [12] .

AD is now recognized as a public health issue [16] , and has kindled considerable interest in the drug industry because it affects one in ten individuals over 65 years, develops spontaneously, is age-dependent, can affect anybody, is incurable, and the patient can live for years with the disease taking medication on a daily basis. Around the world, the number of Alzheimer’s patients is on the rise, driving the need for new research. A good deal has already been discovered about the molecular biology of brain function in neurodegenerative diseases, and many studies have made progress in identifying the causes of the defective protein folding that leads to the production of amyloid plaques, which will surely trigger the discovery of new targets and therapeutic agents. It is hoped that treatments will improve significantly as new mechanisms involved in the pathogenesis are discovered.

As Alzheimer’s disease is a major health issue that is only likely to increase with time (around 4.6 million new cases are reported each year [17] , the primary objective of researchers has been to discover more effective drugs to treat it. Many already exist, but no treatment has yet been found to reverse the progression of the disease or to check the neurodegenerative process [18] .

The first medication approved by the U.S. Food and Drug Administration [19] for Alzheimer’s disease was tacrine, launched in 1993 [20] , whose mechanism consisted of preventing the little remaining acetylcholine from being destroyed by the acetylcholinesterase enzyme, which would increase its concentration in the brain. However, because of the strong hepatotoxicity observed [21] , this drug was abandoned.

The drugs approved and used for Alzheimer’s treatment are shown in Table 1; all are designed to retard and treat its symptoms. They can be split into two groups: anticholinesterases, which enable the production of acetylcholine, and memantine, which is an NMDA (N-methyl-D-aspartate) receptor antagonist that works by regulating the entry of calcium to neurons, reducing neuronal death [22] .

The treatments available for AD are not capable of checking the progression of the disease. As such, research centers and drug companies are keen to discover new medications to modify the metabolism of amyloid substance in some way or to prevent the formation of neurofibrillary tangles, which are found in patients’ brains and are responsible for the advance of the disease. However, this is an as yet unresolved challenge for science, as the mechanisms involved in the development of AD, although much studied, are not yet fully understood [12] [23] .

We chose the Derwent Innovation Index (DII) database to search for patent documents, as this is one of the databases that can be accessed from the Brazilian Ministry of Education’s CAPES portal. It was picked for this purpose because it is internationally recognized and contains over 11 million patent documents filed, published, and sometimes granted in over 40 countries since 1963. One of its main advantages is that for each patent there is a concise abstract written by an expert on the subject. It is also possible to access the primary patent records, which facilitates the retrieval of all the information.

The strategy used was to search for keywords in the titles and abstracts and the International Patent Classification (IPC) of the claim. The period covered was from 1995 to 2012 because of the 18-month period in which patent applications remain confidential. The keywords used were “Alzheimer” and “drug.” The IPC class was selected to pick up patent applications of real interest to the analysis, namely subclass A61P 25/28, which is for drugs for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer’s disease or other forms of dementia.

Once retrieved, the patent applications were exported to the VantagePoint® commercial software package, 8.0 version. This text mining tool is very useful for analyzing raw data because it enables large quantities of data to be processed and allows the data to be manipulated so that the information can be harmonized. In the case of patents, one company will often have different names in the assignee or inventors field, but this was standardized at this stage. Another important function is the cleaning filter, which can be used to eliminate any duplicates of documents and terms that cause ambiguity.

Having harmonized the data, we were able to extract some basic information on the subject of interest, such as the total number of documents retrieved, the main research areas, and the leading countries and companies in the development of the technology, and could make an analysis of developments in the technology sector.

There are some drugs currently in use and many under development that are designed to retard the progression of AD, but there is no treatment capable of completely checking its progress. As one of the purposes of stem-cell therapy is to regenerate or replace tissue, this area of study has been cited as a new way forward for future treatments. Research involving the injection of stem cells into areas of the brain that trigger AD symptoms is being conducted [29] - [33] , which is consistent with the large number of patents related to this kind of therapy.

Gene therapy, whereby functional genes are introduced into cells with defective genes, is also a promising approach. Experimental and pre-clinical studies have focused on the use of gene therapy for treating AD, bringing new hope for patients [34] - [36] .

Recent studies have shown that lithium salts may exert neuroprotective effects. In in vitro experiments, lithium has been found to improve neuronal viability through a combination of mechanisms, which include the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and the synthesis of neurotrophic factors. It is believed that long-term lithium treatment can really retard the progression of cognitive and functional deficits, while also attenuating tau protein hyperphosphorylation, which is implicated in the onset of the disease. Although more research is required in this area, lithium treatment is a promising potential area because it could yield disease-modifying effects [37] - [39] .

Currently used to control cholesterol levels, statins have been studied for their potential in treating Alzheimer’s disease because some researchers believe that when statins reduce cholesterol, they may actually alter the metabolism of the beta-amyloid protein precursor, reducing its production and preventing the formation of the plaques responsible for the onset of the disease [40] - [42] .

Treatment involving vaccines has also been studied with an eye to preventing or retarding the development of the disease in at-risk individuals before or in the first stages of cognitive decline with the hope of stimulating the immune system to prevent beta-amyloid clumping. It is hoped that such vaccines will clear any build-up of amyloid-beta (abeta) peptides in the brain, inhibiting their neurotoxic action. Immunotherapy involves inoculation with humanized monoclonal antibodies with high specificity to abeta peptides. These antibodies clump together, favoring the elimination of these toxic substances. However, it was found in some trials that the vaccines caused brain inflammation, which is being investigated, since vaccines are still among the most promising therapies for the future [43] - [45] .

One of the likeliest causes of AD is thought to be oxidative stress. Researchers are therefore trying to find out whether it is possible to improve protection against the disease through the increased ingestion of antioxidants.

Antioxidants can protect brain cells against damage caused by the toxicity of free radicals. Some research is therefore being done into the ingestion of vitamin E, an antioxidant also known as alpha-tocopherol. Vitamin E has been found to prevent the oxidative damage induced by beta-amyloid in cell cultures, delaying memory deficits in animal models.

Resveratrol, a polyphenol that occurs in abundance in grapes and red wine, also has antioxidant properties, providing neuroprotection. Studies have associated the moderate ingestion of wine with a reduced risk of developing AD. It is believed that resveratrol has powerful anti-amyloidogenic activity.

Other antioxidants also being tested as future drugs are selegiline, vitamin C, selenium, and carotene [46] - [51] .

Some studies have associated this sex steroid with Alzheimer’s disease, showing that the loss of estrogen associated with menopause could be linked to its development, because estrogen has a major neuroprotective and neuromodulatory role. Using oophorectomized animals, researchers have demonstrated that estrogen induces changes in the metabolism of serotonin in areas of the brain that involve cognition. Although several studies have investigated this effect, there is still a good deal of controversy about the effectiveness of steroids as a treatment for AD [52] - [54] .

Drugs with other mechanisms are also being researched as potential treatments. There is evidence that substances called secretase inhibitors have the capacity to block beta-amyloid formation. Studies using gamma- and beta-secretases are being done in different parts of the world. These enzymes are believed to be fundamental in the genesis of the beta-amyloid protein. Treatments using these secretase inhibitors could retard the advance of the disease, since this process involves reducing the production of beta-amyloid, responsible for the formation of the amyloid plaques that are implicated in the disease [55] - [57] .

Curcumin is an anti-inflammatory molecule present in the turmeric root. Epidemiological data demonstrate that there are 4.4 times fewer people in their 70s with AD in India, where turmeric consumption is high, than in the United States. This fact has intrigued the scientific community, and some researchers have demonstrated in in vitro studies that curcumin is indeed capable of fragmenting beta-amyloid plaques. As such, its effect on these plaques is being investigated as a potential future treatment [58] - [60] .

Another possible treatment for Alzheimer’s disease is based on docosahexaenoic acid (DHA). This omega-3 polyunsaturated acid encountered in fish and seaweed and is strongly involved in the formation of the cell membranes of nerve cells, especially synaptic membranes. Researchers have found that newborn rats with DHA deficit present a low cognitive performance, and demonstrate space and time disorientation and impaired learning capacity and memory. It has been shown that DHA is an essential fatty acid for the development of the fetal brain, and researchers suggest that a diet rich in DHA could provide protection for the brain against the production of beta-amyloid [61] - [63] .

Recent evidence indicates that valproic acid―a widely used mood stabilizer―has significant neuroprotective potential for Alzheimer’s disease. Studies on laboratory animals suggest that valproic acid protects neurons against beta-amyloid protein and the damage induced by glutamate, because it helps stabilize intracellular levels of calcium. These findings suggest that valproic acid is a promising agent for combatting the disease [64] - [66] .

Some patients seek out unconventional methods to treat the symptoms of Alzheimer’s disease. One such treatment is ginkgo biloba, a herb that contains two components believed to have medicinal effects: flavonoids and terpenoids with antioxidant properties. Ginkgo biloba has been used in China for millennia and some studies have associated it with cognitive enhancement. Although some patent documents cite ginkgo biloba as a possible AD treatment, its efficacy is yet to be proven [67] - [69] .