Recent Advances in the Treatment of Alzheimer’s Disease

Professor of Neurology, Indiana University School of Medicine

This interview was conducted by Peter Cook, on August 18, 2006.

Introduction

10% of adults over 65 years of age in the US have Alzheimer’s disease (AD); at age 85 and over, the prevalence is 50%. 4.5–5 million individuals in the US already suffer from this disease, and the problem is growing; the elderly population in the US is increasing more rapidly than any other age group.

Traditionally, due in large part to the complexity of the disease, AD has resisted treatment. However, according to Dr. Martin Farlow, recently developed drugs are demonstrating some efficacy, and a number of promising new agents are currently in the early stages of human testing. Few doctors have the breadth of experience in treating and studying AD that Dr. Farlow does. Currently the Clinical Core Leader for the Indiana National Institute of Aging supported Alzheimer Center, he co-founded the Alzheimer’s clinic at Indiana University School of Medicine in 1986, and was involved with one of the first positive trials demonstrating that drug therapy (specifically tacrine) could positively impact cognitive functioning. Dr. Farlow and colleagues also identified the second genetic mutation involved in AD, a mutation that, some time after its discovery, became central in creating a useful transgenic model for the study of the disease. Throughout his career, Dr. Farlow has been deeply involved in a wide array of clinical trials and clinical research on the genetics and treatment of AD.

Causes

While aging plays a large role in the development of AD, Dr. Farlow points out that “there is also a strong genetic component. As many as 20% of cases seem to have familial association.” The major genetic factor identified to date is the apolipoprotein E type 4 allele, which is present in ~15% of the general population.

“Roughly 2% of the population carry 2 copies of the type 4 polymorphism,” Dr. Farlow explains. “If you have 2 copies, your chance of developing AD in your mid- to late-60s is as high as 50%. Those with 1 copy have a 50% chance of developing AD in their mid- to late-70s. If you look at the general AD population, 50% carry 1 or more copies of the type 4 polymorphism.” While there are ongoing efforts to identify other genes involved in AD, environmental factors also clearly play a role. “Elevated cholesterol, insulin resistance, and elevated glucose levels associated with diabetes all have association with AD, and some evidence even points to the involvement of hypertension,” Dr. Farlow says.

The pathogenesis of AD is particularly complex. Researchers believe that extra-cellular amyloid plaques, neurofibrillary tangles, and neuron death all play a part.

“These changes occur first in the parts of the brain associated with short term memory and new learning, such as the hippocampus,” Dr. Farlow says. “Even before you can diagnose dementia, CT and MRI scans show that these changes have already begun. As the illness progresses, the effects spread widely across the cortex.”

Treatment

“The first major approach to treating AD involved blocking the enzyme acetylcholinesterase,” Dr. Farlow says. “Acetylcholinesterase metabolizes the neurotransmitter acetylcholine, which is involved with both memory and learning. Tacrine was the first drug to effectively block acetylcholinesterase, but significant side effects made long-term use difficult.” Three other acetylcholinesterase inhibitors, donepezil, rivastigmine, and galantamine, were developed after tacrine, and all are still used today. According to Dr. Farlow, they are “modestly effective in treating symptoms, and can improve cognitive functioning in 20%–30% of patients. They also appear to mildly improve behavioral symptoms, agitation, apathy, and depressive problems that can occur in patients with AD.” These acetylcholinesterase inhibitors have been mostly tested in, and are FDA approved for use in, patients with mild to moderate AD.

Memantine, an agent with a different mode of action, has been available since 2002. Memantine works on the NMDA receptor, and is a partial antagonist of the excitatory neurotransmitter glutamate. “Too much glutamate may contribute to cell death,” Dr. Farlow says. “Memantine, by blocking glutamatergic action, has been modestly effective in improving symptoms in moderate to severe stage patients with AD.”

Donepezil and rivastigmine have both been tested in combination with memantine, and these combinations appear to produce more favorable results than any of the substances given alone.

Future Directions

There are a variety of medications and approaches to treating AD currently under investigation. “Many of these,” Dr. Farlow explains, “are targeted at either decreasing deposition of amyloid-forming plaques in the brain or targeting and breaking down plaques that have already formed.” Relatively recent research has identified a number of enzymes called secretases that degrade the precursor proteins from which the beta-amyloid protein that forms brain plaques is derived.

“It has been suggested that blocking these enzymes could prevent formation of beta amyloid and would be a good treatment for AD,” Dr. Farlow says. “Over the last 10 years, a number of different drugs have been developed and have gradually worked their way through preliminary studies; some of them are now in phase 1 and phase 2 studies in humans and, I think, these targeted medications show considerable promise.”

A parallel line of research has focused on using immunological approaches to accelerate clearance of beta-amyloid protein. “The first approach was to inject beta-amyloid as a vaccination,” Dr. Farlow explains. “The idea is to stimulate the body’s immune system to recognize the beta-amyloid protein causing development of antibodies targeted toward this protein, and to thus accelerate clearance of this protein and hopefully remove existent plaques as well.” This has been shown successful in animal models and a preliminary study with humans. “There were some problems in the human study with possible less well targeted inflammatory response leading to encephalitis,” Dr. Farlow says, “but composition of the experimental vaccine has been modified to minimize potential for previously seen adverse effects, and I think this approach continues to show promise.” According to Dr. Farlow, there is also growing recognition that developing monoclonal antibodies that target specific parts of the amyloid protein may have a number of advantages over vaccination where appropriate antibodies may not always reliably develop.

“A number of different monoclonal antibodies have been developed over the last half decade that do seem, in animal models, to very effectively target amyloid protein and facilitate reduction or disappearance of plaques.”

“Over the next 2–5 years,” Dr. Farlow says, “I think we’ll have an answer to whether either of these new approaches—interfering with amyloid metabolism by blocking enzymes that create beta-amyloid from the large precursor protein and/or an immunological approach to accelerating clearance of this protein—are effective.”

Disclosure: Dr. Farlow is on the speaker’s bureaus for Eisai, Forest, Novartis, and Pfizer; is a consultant for Accera, Abbott, GlaxoSmithKline, Novartis, Ono, Sanofi, Sepracor, Solvay, Takeda, Talecris/Bayer, and Zapaq; and receives grant or research support from Elan, Eli Lilly, Forest, Ono/Pharmanet, the National Institute of Aging, and Novartis.