Drugs in Development

The first step in drug development is actually the most important—picking the right target. "Plaques being deposited, synaptic function being disrupted, mitochondria being damaged, and transport mechanisms changing. It is a challenge to pick the right target," Dr. Aisen explained.

Much drug research is focused on beta-amyloid. Drugs are being developed to prevent its buildup into plaques through slowing or stopping beta-amyloid production, enhancing its removal, inhibiting the clumping of beta-amyloid into oligomers and plaques, and dissolving existing plaques altogether. A number of other ongoing clinical trials are testing specific agents that target the two enzymes that cleave the amyloid precursor protein (APP) into shorter fragments, one of which is beta-amyloid. The amyloid cascade hypothesis suggests that those enzymes, when they cut APP to form beta-amyloid, execute the inciting event in a chain that may ultimately lead to AD.

Two of those enzymes, beta-secretase and gamma-secretase, are believed to work together to create the beta-amyloid peptides that form plaques in the brain, and are two of the points of intervention targeted by current drug development efforts. Until recently, beta-secretase had been difficult to work with because its shape does not lend itself easily to drug development. Finally, in early 2008, the results of the initial human testing of a drug candidate showed that the treatment was safe and well tolerated by healthy volunteers and led to a reduction in beta-amyloid levels in the plasma. Unlike beta-secretase, gamma-secretase is not a single molecule, but a complex of molecules. Because of this, it may be easier to interfere with its function since its complexity provides many potential targets. But gamma-secretase is essential to many other biological processes in the body, and any potential drug targeting its role in beta-amyloid production would have to work in a way that allows the enzyme to continue to perform its other normal functions.

Additional drug development efforts focus on the beta-amyloid peptide itself. One of the beta-amyloid-busting therapies farthest along in the drug development process is a vaccine currently being tested by Elan Pharmaceuticals, an innovative approach that we'll describe in depth later in the chapter.

Other broad strategies researchers are pursuing include attempts to prevent brain cell dysfunction and death by slowing oxidative stress, averting inflammation, or maintaining blood flow; increasing levels of neuroprotective molecules in the brain; or preserving the intricate network of connections among neurons. Dr. Lennart Mucke, a scientist recognized in the field for approaching Alzheimer's disease from as many angles as possible, thinks that, "in the future we will treat it like we treat other multi-factorial diseases. We will treat it like we treat hypertension, where, as a physician, you try to get away with giving the patient one drug that they can tolerate. Often you can't control the hypertension with one drug, because you get side effects, so you add another drug that has a mechanistically different route of attack. I believe that in the end, since Alzheimer's disease is so multifactorial, we will probably treat it with combinations of drugs. And I wouldn't be surprised if different patients required different combinations."

This suggests that the right path for Alzheimer's disease drug development is to follow every possible avenue and not just the ones that seem most likely to work. As Dr. Marcelle Morrison-Bogorad, the director of the Division of Neuroscience at National Institute on Aging, made clear, "Even if the amyloid hypothesis is correct, it doesn't mean that beta-amyloid is going to be the best or the only point of intervention for drug development. It could be tau, or a number of other therapeutic targets. The results of early-stage clinical trials targeting tau look promising and will be further tested in larger clinical trials."

As the largest funder of research into AD, the National Institute on Aging takes this multifactorial view of the disease very seriously. Dr. Morrison-Bogorad added, "Each piece of the puzzle is a possible intervention target. So our policy at the NIA is to cast a broad net and fund many promising avenues of research apart from beta-amyloid aimed at uncovering processes that contribute to the transition between normal aging and pathological changes resulting in Alzheimer's dementia."

Previous: Developing New Drug Treatments

Next: Practical Challenges

Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.

Beta-Amyloid

Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.

Dementia

A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.

Inflammation

The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.

Oligomers

Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Synapse

The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.

Tau

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Tangles

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Memory

Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease

Cholesterol

Biomarkers

Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.

Pathology

Microglia

Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease

Genetics

Genetics

Normal Aging