In April 2014 there were 315 open clinical trials under way to understand and treat Alzheimer's disease. 42 of these studies were open, human phase three trials, the last step before United States Food and Drug Administration (FDA) approval and marketing. In the decade 2002-2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline).
There are different approaches. One approach is to reduce amyloid beta, for example with bapineuzumab, an antibody in phase III studies for patients in mild to moderate stage; semagacestat, a ?-secretase inhibitor, MPC-7869; and acc-001 or CAD106, vaccines against amyloid beta. Other approaches are neuroprotective agents, like AL-108 (phase II completed); or metal-protein interaction attenuation, as is the case of PBT2 (phase II completed). Yet another approach is to use general cognitive enhancers, as may be the case for memantine, a pharmaceutical approved in the United States and European Union to treat symptoms of moderate-to-severe AD. A March 2015 physical approach utilized ultrasound for penetrating the blood-brain barrier and activating microglial cells, in experimental animals; researchers reported in Science that the essay eliminated a great proportion of amyloid beta and restored memory function. Finally, there are basic investigations on the origin and mechanisms of Alzheimer's disease.
Video Alzheimer's disease research
Treatments in clinical development
Several potential treatments for Alzheimer's disease are under investigation, including several compounds being studied in phase 3 clinical trials. The most important clinical research is focused on potentially treating the underlying disease pathology, for which reduction of amyloid beta is a common target of compounds under investigation.
Immunotherapy to amyloid beta
Immunotherapy or vaccination for Alzheimer's stimulates the immune system to attack beta-amyloid. One approach is active immunization, which would stimulate a permanent immune response. The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.
A Phase IIA study of ACC-001, a modified version of AN-1792, is now recruiting subjects.
One A? vaccine was found to be effective against inclusion body myositis in mouse models.
Passive immunotherapy
Also derived from the AN-1792 immunotherapy program, there is an infused antibody approach termed a passive vaccine in that it does not invoke the immune system and would require regular infusions to maintain the artificial antibody levels. Micro-cerebral hemorrhages may be a threat to this process.
Bapineuzumab, an antibody to amyloid-?, was previously being developed; however, the drug failed in phase 3 clinical trials. The antibody was designed as essentially identical to the natural antibody triggered by the earlier AN-1792 vaccine.
A recent study showed FDA-approved cancer drugs, PD-1 inhibitors, may benefit patients with Alzheimer's disease. The study used a mouse model of Alzheimer's disease and an antibody against PD-1 to demonstrate a statistically significant reduction in amyloid-? plaques and improved cognitive performance.
Targeting the production of amyloid beta peptide
Gamma secretase inhibition
Gamma secretase is a protein complex thought to be a fundamental building block in the development of the amyloid beta peptide. A gamma secretase inhibitor, semagacestat, failed to show any benefit to Alzheimer's disease patients in clinical trials.
Gamma secretase modulation
Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called a selective amyloid beta 42 lowering agent. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide. Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.
Beta secretase inhibition
As of October 2015, Amgen and Novartis had entered into a co-development agreement to progress the oral beta secretase inhibitor CNP520.
Metal-protein interaction attenuation
PBT2 is an 8-hydroxy quinoline that removes copper and zinc from cerebrospinal fluid, which are held to be necessary catalysts for amyloid beta aggregation. This drug has been in a Phase II trial for early Alzheimers and which has reported preliminarily promising, but not detailed, results.
Statins
Simvastatin, a statin, stimulates brain vascular endothelial cells to create a beta-amyloid ejector. The use of this statin may have a causal relationship to decreased development of the disease.
Metabolic correction
This approach is based on the prominent aspect of Alzheimer's disease, which is common for many other neurodegenerative diseases: energy deficit. It has first been noted for the case of insulin insufficiency in the brain of Alzheimer's patients. Because of that Alzheimer's disease has been called Type 3 diabetes and the insulin modification therapies are in pharmaceutical's pipelines.
Other pharmaceuticals
Several other pharmaceuticals are under investigation to treat Alzheimer's disease.
Allopregnanolone
Allopregnanolone has been identified as a potential drug agent. Levels of neurosteroids such as allopregnanolone decline in the brain in old age and AD. Allopregnanolone has been shown to aid the neurogenesis that reverses cognitive deficits in a mouse model of AD.
Angiotensin receptor blockers
A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35--40% less likely to develop AD than those using other anti-hypertensives.
Antibiotic therapy
Several studies using antibiotics in animal models of Alzheimer's Disease indicated that minocycline and doxycycline exerted a protective effect in preventing neuron death and slowing the onset of the disease.
A preliminary trial of antibiotic therapy with doxycycline and rifampin at McMaster University had indicated that it was effective in delaying the progress of the disease: "In conclusion, a 3-month course of doxycycline and rifampin reduced cognitive worsening at 6 months of follow-up in patients with mild to moderate AD." A re-examination of the same data using "AUC analysis of the pooled index showed significant treatment effect over the 12-month period". However, when these preliminary findings were followed up with a subsequent larger trial, they found that "doxycycline or rifampin, alone or in combination, has no beneficial effects on cognition or function in [Alzheimer's disease]."
The possibility that AD could be treated with antiviral medication is suggested by a study showing colocation of herpes simplex virus with amyloid plaques.
Cannabis
There is limited research on the possible use of cannabis to deter cognitive decline and dementia in Alzheimer's disease, with no high-quality results indicating any benefit as of 2015.
Dimebon
Also in July 2008 results were announced of a study in which an antihistamine that was formerly available in Russia, Dimebon, was given to a group of AD patients. The group receiving Dimebon improved somewhat over the 6 months of the study (and this continued for the next six months), whereas those on placebo deteriorated. Unfortunately the consecutive phase-III trial failed to show significant positive effects in the primary and secondary endpoints. The sponsors acknowledged in March 2010 that initial results of the phase III trial showed that while the drug had been well tolerated, its outcomes did not significantly differ from the placebo control.
Etanercept
Etanercept is being studied in Alzheimer's disease. Its use is controversial.
Insulin sensitizers and Intranasal insulin
Recent studies suggest an association between insulin resistance and AD (fat cell sensitivity to insulin can decline with aging): In clinical trials, a certain insulin sensitizer called "rosiglitazone" improved cognition in a subset of AD patients; in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated. Initial research suggests intranasal insulin, increasing insulin levels in the brain with minimal insulin increase in the rest of the body, might also be utilized. Preclinical studies show that insulin clears soluble beta-amyloid from the brain within minutes after a systemic injection in diabetic transgenic mice modeling AD.
Methylthioninium chloride
In July 2008, researchers announced positive results from methylthioninium chloride (MTC), (trade name: Rember) a drug that dissolved Tau polymers. Phase II results indicate that it is the first therapy that has success in modifying the course of disease in mild to moderate AD.
Sigma receptors
Originally considered an enigmatic protein, the sigma-1 receptor has been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery led to the review of many proposed roles of this receptor in many neurological diseases including Alzheimer's.
Translocator protein
A 2013 study showed that translocator protein can prevent and partially treat Alzheimer's disease in mice.
TrkB agonists
R7 is a prodrug of 7,8-dihydroxyflavone, an agonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). R7 is currently in preclinical development for the treatment of Alzheimer's disease.
Maps Alzheimer's disease research
Disease-modifying drug candidates
Non-imaging biomarkers
The most widely used biomarker is the peptide beta-amyloid 1-42 (A?42), which is measured in cerebrospinal fluid. Levels of A?42 has a high agreement with beta-amyloid positron emission tomography (PET) and both methods detect prodromal AD with equally high accuracy.
Studies have also shown that people with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to normal people. Both decreased NAA/Cr and decreased hippocampal glutamate may be an early indicator of AD.
Early research using a small cohort of Alzheimer's disease patients may have identified autoantibody markers for AD. The applicability of these markers is unknown.
A small human study in 2011 found that monitoring blood dehydroepiandrosterone (DHEA) variations in response to an oxidative stress could be a useful proxy test: the subjects with MCI did not have a DHEA variation, while the healthy controls did.
A 2013 study on 202 people at the Saarland University in Germany found 12 microRNAs in the blood were 93% accurate in diagnosing Alzheimer's disease.
Ultrasound therapy
Positive preliminary results in rats with a non-invasive ultrasound technology aimed to clear the brain of amyloid plaques were reported in Science Translational Medicine. An Australian team describes the strategy as beaming ultrasound into the brain tissue. By oscillating at high frequencies, the sound waves combined with blood-borne microbubbles are able to open up the blood-brain barrier, so diminishing the brain defenses for some hours - an interval in which they stimulate the brain's microglial cells into activation (and, also, give drugs or the immune system access to the brain). The team reports having observed an important clearing out in the beta-amyloid clumps, a change attributed to the microglial cells since their function is basically connected with waste-removal; and full restoration of the lost memory and cognitive functions in 75 percent of the mice they tested it on, without concomitant damage to the brain parenchyma (either in the tissue that was surrounding the beta-amyloid plates, or elsewhere). The treated mice are reported to have displayed improved performance in three memory tasks - a maze, a test to make them to recognise new objects, and one to make them to remember the places they should avoid. On these results, the team is planning on starting trials with higher animal models, such as sheep and monkeys, for eventually to have human trials underway in 2017.
Bioinformatics approach
Although in silico studies have advanced our understanding of Alzheimer's disease (AD) in many different areas, there are still limitations to these methodologies because bioinformatics tools are biased toward known data. Nonetheless, the findings obtained from using publicly available bioinformatics tools and databases have provided a mean to discover new treatments and to spark new questions to facilitate the process of finding cures for AD.
Pathogenesis and biomarkers
From gene expression patterns obtained in microarray datasets, correlation between cellular physiology and diseases can be revealed. Divergence studies (e.g. Jensen-Shannon divergence computations which interprets difference in gene expression and probability of distribution patterns) reveals gene expression distribution difference between AD and normal aging brains. That is, expressed genes that are negatively correlated with normal aging brain but are positively correlated with AD brains are possible biomarkers for AD diagnosis and treatment. Combining KEGG and PATHWAY studio, ATP5C1, COX6A1, NDUFV2, PLCB1, and PPP3CA are metabolism and mitochondrial-related genes that have been shown to be reduced in AD samples. Furthermore, metabolic dysregulations such as calcium homeostasis and insulin signaling have also been identified to contribute to the onset of AD. Genes that are associated with calcium and insulin signaling are found using GATHER (online bioinformatics tool for analyzing genomic signatures). In fact, insulin signaling impairment and AD has been considered to be related in many levels. Functional protein sequence alignments (e.g. ClustalW, MUSCLE) and phylogenetic analysis (e.g. Phylip, Mega) demonstrate that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are highly linked in these two diseases. Increased BChE contributes altered lipoprotein metabolism and insulin insensitivity, and is positively correlated to hypertension and diabetes in correlation studies. AChE allows stabilization of neurotransmitter, acetylcholine (ACh), which is one of the main target for AD treatment. However, recent in silico pharmacological study examined drug-disease interaction showed that AChE inhibitors may not be the answer to AD treatment. PKC, ARG, HDAC, and GSK3 inhibitors that regulate calcium homeostasis and genetic modification of cell cycle and apoptosis may be the future targets of AD medication.
Neuronal plasticity is a key player in cognitive function that cannot be ignored in study of AD progression. Microarray studies found that NEFM, NEFL, and SV2B are highly downregulated in samples obtained from severe AD patients. NEFL is a neurofilament gene that has been shown to be related to hypotrophy of axons in motorneurons when mutated. However, both neurofilaments (NEFL and NEFM) have been documented to be involved in neurological disease, Charcot-Marie-Tooth, instead of AD, which demonstrate possible unknown connections of AD to other neurological diseases. SV2B is another gene that is downregulated in AD and has been shown to be related to neurodegeneration, particularly synaptic calcium-regulated exocytosis. The downregulation of genes responsible for neural synapse and neuroplasticity is related to another family of protein that has been found to be related to AD pathogenesis, EGR (early growth response). This EGR is regulated by upregulated FOXO1 (Forkhead Box O1) through PI3K/Akt pathway, which is listed as one of the pathway for future in anti-AD medication. These findings using computational methods allow for the connection of different studies and facilitate the understanding of disease complexity as well as directing to new possible biomarkers of AD.
Pharmacology
The current treatment for AD symptoms are acetylocholinesterase inhibitors and N-methyl-D-aspartate receptor (NMDA) antagonists. Based on the current literature on AD pharmacology research, analyzing differentially expressed genes in drug-drug, disease-disease, and drug-disease models allow discovery of novel pharmaceutical agents that potentially treat more than AD symptoms. Analytical tool such as Connectivity Map (cMap) was utilized in drug-disease interaction from publicly available microarray data. Gene signatures from the cMap-based interpretation showed that common anti-AD drugs (tacrine, donepezil, galantamine, memantine, and rivastigmine) were not listed in the final drug list. Rather, other compounds that inhibit downstream effectors of cell proliferation, Wnt and insulin pathways, epigenetic modifications, and cell cycle regulation were among the top in the final anti-AD drug list. These findings further supported the fact that AD is a disease of degeneration and growth dysregulation. In fact, the final list of anti-AD drugs, obtained from analyzing microarray datasets and cMap drug-disease model contained the common effector of AD and diabetes - glycogen synthase kinase 3 (GSK3-an enzyme that has been found to be related to hyperphosphorylation of tau protein) - confirmed the link between the two diseases. Further pathway and network interpretation of genes obtained from AD microarray datasets using KEGG, WikiPathways, Reactome, Biocarta, and NetworkAnalyst showed that epidermal growth factor (EGF) and its receptors were strongly associated with pathogenesis of AD. EGFR is a transmembrane protein and a member of the HER/ErbB receptor family that share a common pathway with insulin receptors (Ras/Raf/Mak and PI3K/Akt). Furthermore, amyloid protein precursor (APP) was found to be indirectly related based on network analysis. A? (one of the diagnostic findings of AD) activates EGFR and inhibition of the receptor improved memory disorders in A?-overexpressed drosophila. Drugs that block GSK3 were found to be affecting PI3K/Akt pathway, demonstrating that EGFR could be a new target for pharmaceutical agent in treating AD.
References
Source of article : Wikipedia
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