Pharmacological Treatment of Alzheimer’s Disease: Is it Progressing Adequately?

II.A. Drugs to Reduce βA Production

Insoluble βA is formed because γ-secretases (presenilins) and β-secretases (BACE -β-site APP cleaving enzyme-) cut the transmembrane amyloid precursor protein (APP), releasing this intermediate fragment, instead of being done by γ and α secretases, which release the soluble fragment APPs-α (Fig. 5). In the last few years, the strategy of inhibiting γ- or β-secretase has given a hint of hope in the treatment of AD. Most of γ-secretase inhibitors also inhibit the action of this enzyme on the notch protein and other protein substrates that take part in cell differentiation processes and therefore are not well tolerated (they produce alterations in thymus, intestine and spleen in experimental mice) [43-45]. For this reason, allosteric modulators or selective inhibitors of the γ-secretase which acts on the APP are currently being synthesized [45-47]. The γ-secretase inhibitor LY450139 has already started a phase-III trial. In the phase-II trial a tendency towards cognitive improvement and lower βA40 levels in blood and cerebrospinal fluid took place against placebo; however, no significant differences were reached [47]. The inhibitor may also cause eosinophilia and diarrhea and, in one case, death occurred after a digestive hemorrhage due to Barrett’s esophageal ulcer developed during the treatment [47]. Imatinib mesylate (antineoplastic) has shown an inhibiting action of γ-secretase without altering the notch substrate , so that its experimentation in AD has been suggested [48]. Several experts think that the action on β-secretase would be better tolerated, having tested BACE-1 inhibitors (I-BACE1) [49] and antibodies against the BACE cleavage site of the APP [50]. The GSK188909 I-BACE1, for instance, reduces βA load in transgenic mice [51], and CTS-21166 showed good tolerability and plasmatic reduction of βA in a phase I trial with healthy people. Successive generations of I-BACE have gradually obtained structures of low molecular weight and high inhibiting capacity for their possible use in clinical practice [52-60]. Apart from APP, BACE1 also hydrolyzes sialyltransferase ST6Gall (in the Golgi apparatus) and neuroregulin-1, which takes part in myelination processes occurring mainly after birth. Encouraging results have been obtained in BACE1 knockout mice, pointing out that the use of I-BACE in adults might not have negative repercussion [61, 62]. It is foreseeable that broad clinical trials with human patients will be undertaken soon. Among the multifunctional molecules under research, we can mention Memoquin which, apart from being I-BACE1, has antioxidant properties, is an ACEI and reduces βA aggregation and tau-hyperphos-phorylation [63].

Instead of inhibiting β- or γ-secretases, there is the possibility of stimulating the pathway of the α-secretase. Retinoic acid, final product of the metabolic cascade of vitamin A, modulates biological processes of proliferation, differentiation and apoptosis, stimulates the activity of α-secretase ADAM-10, protects from βA toxicity and is reduced in AD [64, 65]. Therefore, retinoic acid analogs such as fenretinide [65] or activators of its PAC1 receptor, such as the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) [66], constitute research elements to slow down the progression of AD. Among the multifunctional drugs which stimulate the non-amyloidogenic pathway of the α-secretase, statins and ladostigil can be included and shall be commented on later.

Some non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen, indomethacin, sulindac, diclofenac (and not others such as acetylsalicylic acid, naproxen, celecoxib and rofecoxib) have shown regulating effects on βA42 production. The mechanism for this action seems to be varied [67], but it mainly consists of the allosteric modulation of the γ-secretase that hydrolyzes the APP, without acting on notch or other substrates [68, 69]. Up to this point, no randomized prospective trials obtaining a significant favorable modification in the evolution of AD through NSAID treatment have been published. Glucocorticoids and celecoxib produce an amyloidogenic effect in some cases, so that it is not probable that their research in AD will continue [70-72]. In a broad epidemiological study a reduction of the risk of AD in individuals with the Apo E-ε4 allele who have been treated with NSAID was observed, but there were no differences according to the fact that the NSAID received was or was not a βA42-reducer [73-75]. On the other hand, knowing the side effects of NSAID (especially gastrointestinal effects), it should be proven that, after long-term administration, the potential modifying effect of AD is not cut short by serious complications. One of the γ-secretase modulating NSAID without action on notch is flurbiprofen. In the phase-II trial it was observed that in the subset of patients with incipient AD (MMSE = 20-26) and high dose of the drug (800 mg bid) significant improvement took place in functional autonomy and a positive tendency was also observed in cognition [76]. In the phase-III study, however, flurbiprofen failed to improve cognitive functioning or autonomy in daily activities.

Cholesterol increases βA-production from APP and, in turn, such increase reduces cholesterol synthesis. Statins inhibit lipidation of β-secretases and through the isoprenylation of GTPase, which takes part in secretases assembly to the APP, reduce βA-production [77, 78]. For this purpose, it is possible that the statins which cross the blood-brain barrier (simvastatin, lovastatin) are more effective than some others such as pravastatin or atorvastatin [79, 80]. They also have anti-inflammatory effects [81] and some of them, such as lovastatin, produce a glycogen-synthase-kinase 3 (GSK-3β) inhibitory effect [82], through which hyperphosphorylated tau protein is reduced and, in fact, less neurofibrillary tangles have been reported in patients who have previously taken statins [83]. The results from epidemiological studies and clinical trials regarding the risk to develop AD or modification of its evolution differ. Therefore, further evidence is needed before statins can be used as protectors against AD [84, 85]. The lipid-lowering drug fenofibrate, unlike statins, has an amyloidogenic effect similar to that of cholesterol [71, 72].

Apart from their sexual function, gonadal steroids exert other functions. Estrogens facilitate APP processing through the non-amyloidogenic pathway, reduce tau-hyperphosphorylation and oxidative stress, and exert a trophic stimulus on cholinergic neurons and other brain cells important in AD [86-91]. Epidemiological studies have observed lower incidence of AD in women who have received treatment with estrogens [92] and lower atrophy in hippocampal regions [93], although observational studies with negative results can also be found [94-96]. Among these, particular emphasis needs to be given to the Women’s Health Initiative Memory (WHIMS) [94], a randomized double-blind study which followed up (through an average of 4 years) 4532 nondemented postmenopausal women older than 64 years, who underwent treatment with conjugated equine estrogen and medroxyprogesterone (n=2229) or placebo (n=2303). Out of the 61 women who developed dementia, 40 (66 %) belonged to the group of active treatment and 21 (34 %) to the placebo group, which means a hazard ratio for probable dementia of 2.05, 45 vs 22 per 10000 person-years (p = 0.01). Participants came from a broader study (Women’s Health Initiative –WHI-) which was suspended in 2002 due to the incidence of adverse events. Discrepancy in the results of the studies is due to multiple reasons, although the main reason might be that estrogens slow the progression of AD only if they act over a prolonged period of time in an early pre-clinical stage, when there is still no significant βA accumulation. In fact, some researchers have observed that the administration of oestradiol to rats when βA₄₂ has already been accumulated exacerbates neurodegeneration [97], and in short-term treatment [92] or in treatment of demented women [98] it no longer produces beneficial effects. In practice, we cannot prescribe this treatment in pre-clinical stages, due to the fact that we do not know markers for this stage. Besides, we should make use of a treatment whose long-term tolerability profile does not involve a high risk/benefit index. Emerging in this search for alternative drugs is the use of leuprorelin. AD patients show higher serum and brain levels of luteinizing hormone (LH), which facilitates APP processing through the amyloidogenic pathway [99]. Leuprorelin, analogous to the gonadotropin-releasing hormone (GnRH or LHRH), reduces LH and, in transgenic mice, gives rise to lower βA-production and cognitive improvement [100]. In September 2005 a phase-III trial began, whose results have not been published yet.

Phenserine is an ACEI that reduces APPs-β and βA production [101] (see Fig. 5). In a preliminary study with 20 patients, cognitive and cortical activity improvement (PET) was observed [102]. However, in two phase-III trials no significant cognitive benefit was obtained. In a post-hoc analysis of the three existing phase-III studies, cognitive improvement was observed in patients who received higher doses (15 mg/day) for more than 12 months, but no significant difference was reached against placebo regarding clinical global impression.

Cerebrolysine is a nootropic agent which reduces apoptosis and facilitates neurogenesis within the hippocampal region in transgenic mice [103]. Through a kinase-inhibiting effect (on GSK-3 and cdk5) it reduces phosphorylated APP, that gives rise to lower βA-production [104]. A meta-analysis of trials carried out so far points out that intravenous infusion 5 days a week for 4 weeks improves clinical global impression, although its effect on cognition and functional autonomy varies; in some studies it is no different than that obtained with placebo [105].

II.B. Drugs to Reduce βA Aggregation

There exist some synthetic peptides (beta-sheet breakers) —for instance, Aβ16-22m, iAβ5, iAb5p, iAb5p-A1, PAB-3631-PI, SEN-304— that attempt to prevent and undo the β-folding which takes place in many βA-fragments in order to reduce its aggregability and inhibit fibrillogenesis [106, 107]. Another strategy is the treatment with monoclonal antibodies aimed at the N-terminal region of βA involved in fibrils precipitation; it obtains fibrillar disaggregation, giving back solubility to the peptide and eliminating its toxicity [108]. All these proceedings still have not reached advanced stages in human experimentation.

Tramiprosate (Alzhemed^®) is analogous to glycosaminoglycans which, through their joint to βA, hinders its aggregation. Unfortunately, in the last phase-III trial no significant clinical efficacy was reported and some researchers noticed that it may increase tau-aggregation [109]. Lipocrine, a hybrid compound of tacrine and lipoic acid, blocks the catalytic binding site of acetylcholinesterase and βA, giving rise to a reduction of βA aggregability as well as having antioxidant properties like the lipoic acid [110]. Colostrinin, derived from calostrum, solubilizes βA-fibres and reduces its polymerization, besides having antioxidant properties. In studies against placebo, it has been observed that it leads to certain cognitive and functional stabilization [111]. Curcumin, a component of culinary curry, crosses the blood-brain barrier and hinders βA aggregation; it is also disaggregating and has anti-inflammatory and antioxidant properties [112]. In a double-blind placebo-controlled trial with 34 patients, no significant clinical differences were observed and βA₄₀ serum levels did not vary either [113].

Some metals take part in intracellular physiological oxidoreductive activity. Their interaction with βA has various effects. For instance, their bind to Cu++ (and Fe+++ to a lesser extent) facilitates the formation of toxic oligomers and the increase of oxidative activity and formation of free radicals, while the presence of Zn++ displaces Cu++ and exerts a protective effect [114]. Therapeutic strategies try to modulate the presence of these metals in the brain in order to reduce oxidative activity, or try to eliminate free radicals already formed by administering antioxidants. A zinc supplement in diet has been suggested, but experimentation points to its inadvisability [115]. Treatment with metal-chelating agents seems to be more plausible. Among the latter, clioquinol (PBT-1) did not obtain sufficiently positive result in the trial [116] and may produce visual alterations. PBT-2 is currently in phase-II of experimentation. It seeks to inhibit the formation of βA-oligomers and disaggregate amyloid plaques through promoting p copper and zinc brain homeostasis.

A phase-II trial with AZD-103 (scyllo-inositol, scyllo-cyclohexanehexol), which reduces βA aggregation and neutralizes oligomers, has already begun. NAP (also known as AL-108), administered intranasally, has also reached phase-II in research as an octapeptide with βA-antiaggregant and microtubule stabilizer properties. Memoquin has been mentioned in Section II.A as a multifunctional compound that reduces the βA aggregability promoted by acetylcholinesterase [63].

II.C. Drugs to Stimulate βA Elimination

A technique to eliminate βA is immunotherapy, which may be active (βA is administered to stimulate the production of antibodies) or passive (anti-βA antibodies are administered). In the first case we find AN1792, whose trial in humans was suspended due to the appearance of encephalitis. In the brain of autopsied patients who generated antibodies, lower than expected βA density was observed, apart from activated microglia and persistence of neurofibrillary tangles [117]. Clinically, no significant improvement against placebo was obtained [118] and greater loss of brain and hippocampal volume was observed through magnetic resonance [119]. The same dementia-progression rate was observed in patients showing βA reduction, perhaps because neuritic plaques are the final product of a neurotoxic process whose greatest responsibility may be attributed to amyloid oligomers, whose formation precedes plaque formation. On the other hand, a faster rate of progression was observed in patients with no amyloid reduction than in untreated patients, which adds fear to the use of this therapeutic technique. However, such line is still being researched; ACC 001 and CAD-106 (in phases II and I, respectively) are two formula of active immunotherapy that attempt to act without causing brain defensive reactions. Among monoclonal anti-βA antibodies we find AAB 001 (bapineuzumab). A study refers brain micro-hemorrhages in patients who underwent passive immunotherapy, so that further attention should be drawn to its tolerability [120]. The preliminary results of a phase-II double-blind trial with intravenous immunoglobulins against placebo in 24 AD patients for 6 months, showed better evolution in clinical global impression (p < 0.001) but no significant difference was reached regarding cognition (paper presented by N. Relkin et al. at the 60^th Annual Meeting of the American Academy of Neurology, April 2008).

Insulin accelerates βA intracerebral circulation and elimination, and increases of the brain insulin resistance have been reported in many AD patients. Showing insulin resistance during midlife increases the risk of suffering AD in subsequent years [121]. For this reason, the effectiveness of rosiglitazone has been researched; it reduces such resistance, is anti-inflammatory and stimulates mitochondrial biogenesis [122]. In a double-blind placebo-controlled trial (n=518) cognitive improvement was only observed in the group of patients without the APO E ε4 allele [123] and, in another study in which 30 patients were followed up for 6 months, those patients who received rosiglitazone did not show the diminution of βA in cerebrospinal fluid shown by the placebo group [124]. It seems to be necessary to widen experimentation with this substance as well as to check to what extent it produces in AD patients the same cardiovascular events it causes in diabetes patients [125]. Intranasal insulin has also been researched since it increases glucose availability in the brain, scarcely affecting its peripheral metabolism. In a placebo-controlled study (n=25) treated patients showed better results regarding attention, memory and functional capacity [126]. As it occurs with rosiglitazone, it seems that the treatment is only effective in patients without the APO E ε4 allele [127].

Curcumin, already mentioned in the previous section, binds to amyloid deposits and facilitates their elimination [112], although such action produced no significant clinical or serum βA changes in a narrow trial [113].

Stimulation of plasminogen through tPA (tissue plasminogen activator) and the subsequent generation of plasmin reduces βA formation and accelerates its elimination. For this reason, the possible usefulness of a treatment with PAI-1 (PAI = plasminogen activator inhibitor) or TGB-β1 (PAI-1 inductor) inhibitors or antagonists has been raised [128]. It has also been observed, however, that tPA induces the activation of GSK3 and, thus, greater tau-phosphorylation and neurotoxicity [129], so that the application of the above mentioned treatment may turn out to be risky.

Somatostatin modulates βA-proteolysis mediated by neprilysin. In AD, a somatostatin depletion facilitates βA-accumulation. Drugs analogous to somatostatin (e.g. octreotide, ineffective in AD [130]), drugs which stimulate somatostatin release (for instance FK962, ineffective in a phase-II study) or drugs that act on its receptors, have been considered as candidates for experimentation aimed at improving the evolution of AD [131, 132].

II.D. Drugs to Reduce Neurofibrillary Degeneration

Phosphorylated tau-protein binds to microtubules in order to facilitate their assembly, assuring the stability of the neural cytoskeleton. A correct phosphorylation requires a balance between the action of some kinases and phosphatases (especially GSK 3, cyclin-dependent protein kinase —cdk5— and protein-phosphatase 2A —PP-2A—). GSK-3β plays a more relevant role than GSK-3α in tau-phospho-rylation, while the opposite occurs in APP processing to produce βA. There is a GSK3 hypothesis of AD, according to which GSK-3 hyperactivity would be responsible for excessive βA-production, periplaque microglia reaction and tau-hyperphosphorylation. The latter, in turn, alters axonal transport, reduces the firmness of the cytoskeleton and induces the formation of neurofibrillary tangles [133]. An increase of endogenous inhibitors of PP-2A in AD has also been observed [134]. From a therapeutic viewpoint, it may be possible to inhibit GSK-3 or stimulate PP-2A, having identified subgroups of AD that may respond differently to these treatments [135]. Molecules with anti-GSK3 properties have been investigated in antineoplastic research, some of them being suggested to be applied to AD, such as certain derivatives of indirubin [136], paullones [137], aloisines [138] or hymenialdisine [139]. Lithium and valproic acid have also been studied as GSK-3 inhibitors [140]. Valproate does not act on cortical GSK-3 [141] and, regarding lithium, some researchers think that it acts on GSK-3β and GSK-3α and, due to its action on the latter, reduces βA-production [142], while other researchers have observed βA-increases, which they attribute to a mechanism not related to GSK3 [143].

Among the multifunctional drugs with anti-GSK3 action, the afore-mentioned lovastatin [82] and thiadiazolidinones can be cited. The latter have anti-inflammatory and neuroprotective effect, partly because they activate nuclear peroxisome proliferator-activated receptors (PPAR) and partly because they inhibit GSK-3β [144, 145].

Nicotinamide (vitamin B3) produces cognitive improvement and phospho-tau reduction, mediated by its action on kinases, in transgenic mice (paper presented by KN Green et al. at the 60^th Annual Meeting of the American Academy of Neurology, April 2008). Therefore, it is a candidate molecule to be valued in AD patients, maybe as a complement to other treatments.

On the other hand, memantine stimulates PP-2A, thus contributing to the reduction of neurofibrillary degeneration [39, 40].

Paclitaxel, which is related to taxol, stimulates tubulin polymerization and acts as a microtubule stabilizer [146].

Currently, active immunotherapy with phosphorylated tau is under research. The generation of antibodies that reduce neurofibrillary tangles with no inflammatory reaction has been observed in animals [147].

II.E. Drugs to Reduce Excitotoxicity and/or Oxidative Stress

Glutamate excess in synapses in diseased brain areas has deleterious effects for the cell (excitotoxicity). It causes excessive entrance of calcium into the cell, with an increase of the oxidative activity and functional damage to mitochondrias. LY451395, a modulator of glutamate AMPA receptors, did not reach significant clinical differences against placebo in a trial [148]. Dimebolin hydrochloride (Dimebon®) is an acetyl and butyrylcholinesterase inhibitor that blocks the entrance of calcium through L-type (voltage-dependent) and NMDA (glutamatergic) channels, having symptomatic and neuroprotective effects [149, 150], and modulating mitochondrial membrane pores, so that it helps preserve mitochondrial function [151]. In a one-year-long double blind, placebo-controlled, phase-II study with 183 patients, significant improvements in cognition, behavior and functional autonomy were observed [152]. Patients are currently being enrolled in a phase-III study (http://www.alzforum.org/new/detail.asp?id=1590;; http://www.medivation.com). Memantine is the antagonist drug of NMDA receptors that has given us the greatest amount of results within the field of AD. The reduction of excitotoxicity and of oxidative damage is one of its main functions [153]. Its proven symptomatic effect [5-10] and the fact of reducing tau-hyperphosphorylation [39, 40] make it an interesting drug with which to treat AD. Anyway, it will be necessary to prove its possible modifying effect in AD evolution through trials specifically designed for such aim. Other new-generation anti-NMDAs such as neramexane are currently being researched for neuroprotection in AD [154]. No significant differences were observed in a phase-III trial with 415 patients in which double-blind comparisons were established between a single anticholinesterase or a combination with neramexane; this research is ongoing with the administration of such drug as monotherapy against placebo.

Drugs with antioxidant action such as memoquin, lipocrine, colostrinin, curcumin, rosiglitazone, clioquinol or PBT-2 have already been mentioned in previous sections due to their multifunctional capacity. Some epidemiological and prospective studies observe lower AD incidence or progression in individuals taking vitamin E, preferably in combination with vitamin C [155-157], but a Cochrane analysis does not find clear evidence of any beneficial effect [158]. Furthermore, a meta-analysis showed an increase of mortality in individuals taking more than 150 UI/day of vitamin E [159]. Ginkgo biloba has antioxidant effects, but the most recent trials have failed to find any benefit on progression of cognitive impairment or AD [160-162]. Furthermore, such treatment is not free from a small risk of ischemic or hemorrhagic events [162, 163].

Melatonin has antioxidant and antiapoptotic properties, it increases mitochondrial energetic metabolism and reduces tau-hyperphosphorylation and βA-formation and deposit [164, 165]. Moreover, its MT1 and MT2 receptors are altered in AD [166]. Experimentation in AD animal models leads us to think of a favorable clinical effect of melatonin, but no controlled extensive clinical trial have been carried out in humans in order to demonstrate if melatonin can modify AD incidence or progression. Likewise, tacrine-melatonin hybrid molecules, which presumably would add the symptomatic effect of the anticholinesterase to the combination, are currently under research [167].

Studies developed with selegiline, an IMAO-β with antioxidant properties, conclude that there is no justification to use it in AD patients [168]. Rasagiline has different aspects from selegiline that make it more attractive, apart from facilitating APP non-amyloidogenic processing [169]. AD research, however, seems to have moved towards a bifunctional molecule, ladostigil, that combines properties of rivastigmine and rasagiline [169, 170].

Higher cortisolemia and greater cortisol/DHEA (DHEA = dehydroepiandrosterone, antiglucocorticoid) ratio are observed in the plasma of some AD patients than in healthy individuals of the same age [171], which may facilitate cognitive impairment and hippocampal atrophy [172]. For this reason, DHEA has been considered as a potential treatment of AD, since it reduces excitotoxicity and has antioxidant properties [173, 174]. In a narrow double-blind placebo-controlled study of DHEA, no significant differences were observed either in cognitive performance or in clinical global impression [175].

Huperzine A, an alkaloid of the herb huperzia serrata used in Chinese traditional medicine, has antioxidant properties, is an ACEI, stimulates muscarinic and neuronal growth factor receptors, increases APP non-amyloidogenic processing, protects against apoptosis and cytotoxicity caused by βA, glutamate or ischemia. In clinical trials carried out in China, it has been observed that it produces memory improvement in elderly people with amnesic disorder and in AD patients or those with vascular dementia, probably due to its ACEI action [176]. It would be desirable to see if its neuroprotective effects lead to favorable modifications in AD evolution. It is currently under a phase-II trial in USA.

A technique to increase the efficacy of already existing treatments is dimmer’s synthesis. Among them we can mention bis-tacrine (tacrine dimmer) and bis-HupA or bis-hupyridone (dimmer of a fraction of huperzine A). Bis-tacrine also has BACE-1 inhibitory action and blocks NMDA receptors, that provides it with an additional neuroprotective action [177].

Polyunsaturated fatty acids facilitate neuroplasticity in neuronal membranes and synaptic transmission, have antioxidant and antiapoptotic properties, protect against excitotoxicity, inhibit the production of proinflammatory cytokines and, furthermore, reduce βA and phospho-tau production while improving learning capacity [178-182]. These fatty acids are not synthesized in the brain but come from food. In animal models and in humans it has been observed that diets rich in these substances or containing a supplement of them (omega-3 fatty acids, docosahexaenoic acid) reduce AD risk, especially in individuals who do not carry the Apo E ε4 allele [183, 184], though some researchers have obtained negative results [185]. These products are available in the market as nutritional supplement. In a small group of AD patients a significantly favorable effect was observed in cognition (MMSE) from treatment with omega-3 fatty acids plus lipoic acid –antioxidant- (paper presented by L. Shinto et al. at the 60^th Annual Meeting of the American Academy of Neurology, April 2008).

Propentofylline is a xanthinic derivative which inhibits adenosine reuptake and phosphodiesterase. Among other actions, it reduces the production of free radicals and microglia activation, stimulates the synthesis and release of the nerve growth factor, facilitates APP non-amyloidogenic processing and decreases activated GSK-3β [186]. The results from phase-II and III trials point out that improvement in cognition, global function and functional autonomy is achieved and the follow-up of individuals who left the study seems to indicate that propentofylline slows down AD progression [187, 188]. In a phase-II study it was observed that brain metabolism (PET) increased after stimulation with a verbal task [189]. However, the authors of the Cochrane analysis point out that part of the data obtained through experimentation has not been published by the researchers and that much of the published data does not discriminate between different etiological types of dementia [188]. The research of this drug in relation to AD has been interrupted.

II.F. Cell Therapy, Regenerative Medicine

The incorporation of multipotential cells into the brain to stimulate neurogenesis in brain areas affected by AD (cell therapy) is a promising field. In animal models, implanted cells undergo intracerebral migration, differentiate themselves and improve memory [190]. For multiple reasons, the treatment is complex. The optimum source of stem cells that should be implanted is a question currently under public and scientific debate. The implantation technique needs to minimize risks. The implanted cells should not only survive but they also need proliferate, differentiate themselves by acquiring the specialization of affected cells and, finally, integrate themselves in complex cell networks in order to make their function operative. The use of out-of-patient multipotential cells (obtained from embryonic tissues, bone marrow, umbilical cord or placenta, for example) may induce rejection more easily than using the patient’s own cells. In this sense, nerve cells have already been obtained from the patient’s skin or bone marrow [191]. Embryonic stem cells have great replication capacity but they also present a great risk for developing tumors [192]. An alternative consists of activating (through genetic modifications or nerve growth factors) stem cells which are inactive whether in the own brain or in another part of the body [191, 193, 194]. Moreover, this procedure avoids the surgery required to implant exogenous cells. A recent trial showed that stem cells administered intravenously to transgenic mice cross well the blood-brain barrier; this might solve the problems associated with implantation surgery [195]. On the other hand, if there is an excess of APP in the brain, multipotential cells become glial cells to a greater extent than neuronal cells (thus producing gliosis), so that it would be necessary to modulate the presence of APP. A variant of phenserine has been tested with such aim [196, 197]. Interesting to note is the study in which 6 AD patients were followed up for 22 months after being implanted genetically-modified autologous skin fibroblasts in order to produce human nerve growth factor. The results range from a slower progression of cognitive impairment to an increase of cerebral cortical activity (PET) [198].

Many of us, who are engaged in neurological clinical practice and are mere observers of this matter, suspect that other problems are much more difficult to solve:

1. AD affects extensive associative and limbic areas of the brain as well as multiple subcortical gray-matter nuclei, which are the source of several neurotransmitters. Therefore, treatment with stem cells should act on various points and new cells should acquire varied specializations.
2. When associative areas formed by axon and dendrite tangles of varied origin are affected, it seems difficult for newly arrived cells to properly integrate their new tentacles (both structurally and functionally) in such complex networks.
3. Stem cells which begin to specialize within the diseased brain will have to do it in a hostile environment. When the first symptoms appear, several alterations —which include the activation of microglia and other inflammatory elements, accumulation of neuroexcitatory aminoacids, deposit of proteins with neurotoxic effects, etc.— have already been taking place in the brain for many years and many surviving cells are also functionally damaged, all of which hinders the development of implanted cells.

In short, it seems more feasible to introduce cells into the brain intending to stimulate the production of neuronal growth factors or the secretion of deficient neurotransmitters, instead of cells that attempt to substitute degenerated brain tissue.

On the other hand, knowing the possibility of creating transgenic mice, we may attempt to correct mutations and polymorphisms that cause the disease or increase the risk to suffer from it. This genetic manipulation is very difficult to apply in sporadic AD, since there are many genetic risk elements (many of which are still unknown) and difficulties of an ethical nature will be found in monogenic hereditary forms. In any case, what today seems to be utopian may become a pleasant reality within the not-too-distant future. However, the path currently followed by cell therapy and genetic manipulation and engineering to treat degenerative dementia may prove to be both thorny and lengthy.