Alzheimer's disease research

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.

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 γ-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 moderate-to-severe AD. A recent (March 2015) physical approach utilizes ultrasound for penetrating the blood-brain barrier and activating microglial cells, in experimental animals; researchers reported in Science that the essay eliminates a great proportion of amyloid beta and restores memory function. Finally, there are basic investigations on the origin and mechanisms of Alzheimer's disease.

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 Aβ 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.

The most advanced such candidate is known as bapineuzumab or aab-001, and this antibody is designed as essentially identical to the natural antibody triggered by the earlier AN-1792 vaccine. The aab-001 antibody is in Phase 3 clinical trials for both Apolipoprotein E4 gene carriers, and Apolipoprotein E4 gene non-carriers.

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.

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

Only one clinical trial is being done (at McMaster University) to investigate the efficacy of antibiotic therapy. The authors of the study 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".

Several studies using minocycline and doxycycline, in an animal model of Alzheimer's Disease, have indicated that minocycline and doxycycline exerts a protective effect in preventing neuron death and slowing the onset of the disease.

Antiviral therapy

The possibility that AD could be treated with antiviral medication is suggested by a study showing colocation of herpes simplex virus with amyloid plaques.

Cannabinoids

The endocannabinoid system may have a role in AD. For instance, THC, one of the active ingredients in marijuana, has been show to reduce amyloid beta plaque formation through inhibition of acetylcholinesterase (AChE).

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.

The United States Food and Drug Administration (FDA) has approved an intranasal insulin device.

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.

Disease-modifying drug candidates

Disease-modifying candidates in late-stage clinical trials for Alzheimer's disease

Target/Approach	Notes (Theoretical)	Candidate Name	Trial Phase	Trial Start Date	Expected End Date	Planned Enrollment	AD population targeted (severity)	AD population targeted (genetic)	Comments
Gamma Secretase Modulator/NSAID	Shifts amyloid beta production to shorter and less toxic species. Targets γ-secretase.	Flurizan (R-flurbiprofen, MPC-7869)	Phase III (completed)	Feb 2005	May 2008	1,600	Mild	n/a	Myriad Genetics concluded that the drug did not improve thinking ability or the ability of patients to carry out daily activities significantly more than those patients with placebo. Peter Meldrum, CEO of Myriad Genetics, announced on June 30, 2008 that the company will no longer be developing Flurizan
Gamma Secretase Inhibitor	Inhibits Gamma Secretase, which reduces amyloid beta levels	Semagacestat (LY450139)	Phase III (completed)	Sep 2008	Apr 2011	1,100	Mild-to-Moderate	n/a	On August 17, 2010, Eli Lilly announced that it "will halt development of semagacestat" as it "did not slow disease progression and was associated with worsening...cognition and the ability to perform activities of daily living." Also, it is "associated with an increased risk of skin cancer."
Antibody to amyloid beta	Mimics natural antibody triggered by AN-1792	Bapineuzumab (aab-001)	Phase III (completed)	Dec 2007	Apr 2012	1,121	Mild-to-Moderate	Apolipoprotein E4 Carriers only	On August 6, 2012, Pfizer and Johnson & Johnson said they are "ending development of an intravenous formulation" of bapineuzumab. Phase III trials "showed no treatment effect on either cognitive or functional outcomes. Biomarker analyses indicated that bapineuzumab engaged its target, but had no benefit."
Antibody to amyloid beta	Mimics natural antibody triggered by AN-1792	Bapineuzumab (aab-001)	Phase III (completed)	Dec 2007	Jun 2012	1,331	Mild-to-Moderate	Apolipoprotein E4 Non-Carriers only	On August 6, 2012, Pfizer and Johnson & Johnson said they are "ending development of an intravenous formulation" of bapineuzumab. Phase III trials "showed no treatment effect on either cognitive or functional outcomes. Biomarker analyses indicated that bapineuzumab engaged its target, but had no benefit."
Metal-Protein Interaction Attenuation	Primary targets are copper and zinc. Removes copper and zinc from cerebrospinal fluid.	PBT2 (8-hydroxy quinoline)	Phase II (completed)	Dec 2006	Dec 2007	80	Early Alzheimer's disease	n/a	"Did not meet its primary endpoint of a statistically significant reduction in the levels of beta-amyloid plaques in the brains prodromal/mild Alzheimer's disease patients." "No improvement was observed on the secondary endpoints of brain metabolic activity, cognition and function; however, there was a trend towards preserving hippocampal brain volume". "Specifically, there was less atrophy relative to the placebo group."
Fibrilization of amyloid beta	Breaks down neurotoxic fibrils, allowing amyloid peptides to clear the body rather than form amyloid plaques.	ELND005 (AZD-103, scyllo-Inositol)	Phase II (completed)	Dec 2007	May 2010	353	Mild-to-Moderate	n/a	Phase I produced encouraging results by August 2007. In December 2009, Elan and Transition jointly reported that the Phase II study has been modified so that only the 250 mg twice daily dose will be continued due to "greater rates of serious adverse events, including nine deaths," in the higher dose groups (1000 mg and 2000 mg dosed twice daily). It has received fast track designation from the U.S. FDA.
Neuroprotection	Neuroprotective Peptide, intra-nasal	AL-108	Phase II (completed)	Jan 2007	Jan 2008	120	Mild Cognitive Impairment	n/a	Deemed a Success; Phase III to start
Brain Cell Apoptosis Inhibitor	Operates through multiple mechanisms: Blocks the action of neurotoxic beta-amyloid proteins and inhibits L-type calcium channels, modulates the action of AMPA and NMDA glutamate receptors, may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores, and blocks a number of other receptors, including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6	Dimebon (Latrepirdine)	Phase II (completed)	Sep 2006	Nov 2007 (actual)	183	Mild-to-Moderate	n/a	In March 2010, Pfizer announced that the Phase III CONNECTION trial failed to meet its primary and secondary endpoints. In January 2012, it was announced that the Phase III CONCERT study did not meet its co-primary endpoints. Both CONTACT and CONSTELLATION trials were terminated. Medivation and Pfizer discontinued development of dimebon and thus decided to end their co-development and marketing collaboration.
Natural Antibodies to amyloid beta	human plasma source limits supply	IVIg	Phase II (completed)	Feb 2006	June 2007	24	Mild-to-Moderate	n/a	Deemed a Success; Phase III to start
Vaccine to amyloid beta	Injects modified amyloid beta (active vaccine)	acc-001	Phase II	Nov 2007	Mar 2012	228	Mild-to-Moderate	n/a	Sequel to famous AN-1792 Vaccine Trial

Physical (non-pharmacological) preclinical essays

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.

Non-Imaging biomarkers

Recent studies have 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.

Mouse model

A scanning ultrasound treatment fully restores memory function in 75% of an Alzheimer's disease mouse model. The scanning ultrasound removes amyloid-β.