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Alzheimer's Disease: Update on Recent Developments
Regarding Clinical Treatment Trials and Biomarkers


Michael Rafii, M.D., Associate Medical Director

A number of promising new treatments for Alzheimer's disease (AD) have migrated from early development in the laboratory to being tested in humans. Research has provided a much more complete understanding of the processes that lead to the production and removal of Beta-amyloid protein (Aβ), the substance that forms sticky plaque deposits in the Alzheimer brain. Many scientists believe that Aβ is a molecule that initiates a cascade of damage in AD, and lowering Aβ levels in the brain is an important goal of treatment. Another approach is to target pathways related to tau, a protein that forms the other hallmark brain pathology of AD, the tangle. Basic research advances have provided methods to screen for new drugs that affect Aβ or tau and to test candidate drugs in animal models that express features of AD pathology. Recent areas of interest include the following:

Eli Lilly, Inc. has performed research focused on gamma-secretase, an enzyme which cuts the parent protein of Aβ and many other proteins in the body. This enzyme may contribute to the abnormal cleaving and depositing of Aβ in persons with AD. Eli Lilly is working on a "gamma secretase inhibitor" (LY450139) that has shown promise in lowering Aβ production and decreasing plaque build-up in animal models. In a recently completed multi-center study in patients with mild-to-moderate AD, this drug appeared to be reasonably safe. It lowered the levels of Aβ in the blood for several hours after each dose. Some side effects were noted, but were not major, and a more comprehensive Phase III trial is currently underway.

Elan Pharmaceuticals, Inc. has pioneered approaches to reduce the build-up of Aβ in the brain by using antibodies. Initial studies showing that after mice had been genetically engineered to deposit Aβ in their brains were immunized with Aβ, they raised a strong immune response and made antibodies against Aβ that markedly reduced the build-up of brain amyloid and plaques. In 2002, Elan attempted an immunization study in humans using the Aβ peptide. This trial was stopped after approximately 6% of patients on active treatment developed brain inflammation. A long-term follow-up study on many of the study participants has been encouraging. Of those participants who were contacted, responders showed better performance on cognitive test scores and activities of daily living compared to placebo-treated patients. A series of studies is now underway in which patients are infused with anti-Aβ antibodies ('passive immunization"). To date, these infusions have been safe in patients with mild AD. A Phase II trial is currently recruiting.

Many other investigators are also studying approaches to active immunization, some of which may be safer than the methods in Elan's 2002 clinical trial. The ADCS is conducting a Phase III clinical trial of intravenous Immunoglobulin (IgIV) infusions in AD, aimed at helping to remove Aβ and decreasing inflammation. Information on ADCS sites conducting this study can be found at:
http://www.adcs.org/Studies/IGIV.aspx.

A small initial clinical trial in patients with AD was carried out by Dr. Mark Tuszynski at UCSD using nerve growth factor, or "gene therapy". Patients' skin cells were initially harvested and used to grow cells called fibroblasts in the laboratory. These were injected with the gene that makes nerve growth factor. The fibroblasts were then injected into the brains of patients with AD by a neurosurgeon. Initial data suggested that there may have been a slight improvement of symptoms in some of the study participants. This approach has been extended, using a type of virus with the nerve growth factor gene attached, to deliver the NGF gene to brain cells. Although this approach again requires injection into the brain, it is technically easier and may lead to longer lasting gene expression in the brain. The Phase II trial is now underway. Information on ADCS sites conducting this study can be found at:
http://www.adcs.org/Studies/NGF.aspx.

Omega-3 fatty acids, typically deficient in the American diet, are essential for human health. Docosahexaenoic acid (DHA), in particular, is vital to proper brain function and is the most abundant fatty acid in the brain. In recent years epidemiologists have tied fish-rich diets to a lower incidence of AD and homed in on DHA as the preventive factor. Having increased DHA levels in the blood and eating about three fish meals each week appears to be associated with a significant reduction in the risk of AD. The ADCS has now completed a Phase III clinical trial to study the effects of DHA in patients and results are forthcoming.

Amyloid is known to bind to Receptors for Advanced Glycated Endproducts (or RAGE, for short) on the surface of cells (e.g. the brain’s nerve cells and microglial cells) and at the blood brain barrier. This binding may trigger inflammation and damage to nerve cells. However, by blocking Amyloid-RAGE binding, researchers have found that plaque formation was reduced in animal models. PF-04494700 is an orally bioavailable small molecule antagonist of the RAGE. The drug has been tested in animals, in small Phase I safety studies in healthy volunteers, and in a preliminary short safety study in AD patients. It is now being investigated in a larger Phase II clinical study to determine its efficacy.

Although much is known about the tau protein, it is still not clear exactly how tangles form. Adding phosphate groups to tau is an important regulatory pathway that may influence tangle formation. There are several currently available drugs that can alter tau phosphorylation. One of these, valproic acid, is being studied in a clinical trial run by the ADCS. Another drug, with a stronger effect on these pathways, is Lithium, which has been used for many years to treat bipolar disorder. Treatment with lithium has been shown to decrease tau deposits in an animal model.

Dimebon, another oral agent, is an interesting molecule whose mechanisms of action remain under study. It first came to attention as a drug with neurotransmitter actions (non-selective antihistaminic, weak cholinesterase inhibitor, weak NMDA receptor antagonist) because it had been used in a pilot study for AD patients in Russia. Later, additional, possibly neuroprotective actions, have been discovered, such as a protective effect on mitochondria under conditions of stress. Dimebon has been used in a recently completed Phase II study conducted in Russia, and showed benefits compared to placebo on multiple outcomes including cognition, global abilities, functional abilities, and behavior at six months. In a blinded six-month extension of the study, the benefits persisted for a year and in many cases the difference between drug-treated patients and placebo-treated patients widened over time. A global Phase III study of oral Dimebon in patients with mild-to-moderate AD is currently underway.

Neuroglobin is a protein that was first identified in 2000. It is a member of the globin family, similar to hemoglobin (which carries oxygen inside red blood cells) and myoglobin (which carries oxygen inside muscle cells). It is a highly conserved protein, meaning that it is a very important protein in all species ranging from mice to humans. It is known to be activated by cerebral ischemia (decreased brain oxygen) and is known to protect neurons from such injury.

Despite its ability to bind to oxygen, like hemoglobin and myoglobin, neuroglobin is unlikely to function as an oxygen delivery system. Instead, it seems to be involved in scavenging reactive oxygen molecules (oxidants) generated in response to brain ischemia and injury. Many researchers believe antioxidants are beneficial in various neurodegenerative diseases.

Recent work had shown that neuroglobin decreases beta amyloid neurotoxicity in animal models of AD. Now, a paper from a group at The Johns Hopkins University (Szymanski et al, Neurobiology of Aging, 2009), shows that variations in the gene for the neuroglobin protein may in fact increase one's risk of developing AD by producing inefficient neuroglobin. This inefficient protein is unable to defend against the toxicity of beta amyloid.

More work will be needed to determine if neuroglobin can be affected in a positive way to reduce beta amyloid toxicity in AD patients and if it may be helpful in making a diagnosis of AD.