Alzheimer's disease clinical research

Overview
As of 2008 there were more than 400 clinical trials underway to understand and treat Alzheimer's disease. Over one hundred of these studies were in the last phase before commercialization (phase three trials).

Many different investigation approaches coexist. Amyloid beta is a common target, existing many trials which aim to reduce it with different agents such as bapineuzumab, an antibody in phase III for patients in the mild to moderate stage, MPC-7869, or acc-001, a vaccine to amyloid beta in phase II to be used in the mild stage. 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). Finally, there are also many basic investigations trying to increase the knowledge on the origin and mechanisms of the disease that in the future may help to find new treatments.

Treatments in clinical development
Multiple potential treatments for Alzheimer's disease are currently 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.

History of immunotherapy to amyloid beta
Immunotherapy or vaccination for Alzheimer's is one anti-amyloid alternative under study. Unlike vaccines which seek to prevent disease, this therapy would be used to treat diagnosed patients, and is based upon the concept of training the immune system to recognize, attack, and reverse deposition of amyloid, thereby altering the course the disease.

Following promising pre-clinical work in genetically-altered mice which showed compelling results, the earliest small trials in humans using the vaccine known as AN-1792 suggested some promise and little safety concerns. However, in 2002 a subsequent Phase II trial using this drug reported that 6% of multi-dosed participants (18 of 300) developed serious brain inflammation symptoms resembling meningoencephalitis; as a result and the trial was stopped, and clinical development on AN-1792 was discarded.

In further years, participants in the AN-1792 trials continued to be observed, and it was determined that 20% of treated patients had developed high levels of antibodies to beta-amyloid, which was in itself an interesting result given that on average patients had received only 2 of the planned 8 drug doses. 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.

Active immunotherapy
Directly based upon the AN-1792 immunotherapy approach, in mild-to-moderate AD there are now similar so-called active vaccines being tried, so-called because they actively trigger the body's response, potentially indefinitely once amyloid beta is recognised by the immune system.

The most advanced such active vaccine, called aac-001, is a modified version of AN-1792, and is intended to trigger the same natural antibodies to beta-Amyloid. It is possible that meningoencephalitis-like inflammation remains a potent threats to this strategy.

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-cererebral 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 known as LY451039 is in Phase 3 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. Note that of all the clinical trial programs for AD pathology, this drug candidate is the most advanced, with final results expected in 2008.

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 be have a causal relationship to decreased development of the disease.

Other
Several other pharmaceuticals are under investigation to treat Alzheimer's disease. A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with Alzheimer's disease after treatment with etanercept, a Tumor necrosis factor-alpha receptor fusion protein, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue. Etanercept was administered by perispinal infusion to 15 AD patients which resulted in sustained improvement in cognitive function; however it is not clear if this was temporary or not. A small trial consisting of 50 patients has commenced injecting etanercept, a TNF (tumour necrosis factor) inactivator, into the spine.

Antibiotic therapy in Alzheimer's disease

Only one clinical trial has been done 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.