Combating Alzheimer’s Disease
A Medication Update

By Barbara Worthington

Although clinical trials on Alzheimer’s disease treatment offer hope for the future, there’s no cure for this insidious disease. However, several drugs have been successful in slowing its progression.

Statistics surrounding Alzheimer’s disease (AD) paint a bleak picture of prospects for aging, particularly among the huge baby boomer demographic. The direct and indirect costs of AD and other dementias amounted to more than $148 billion in 2007, to say nothing of the devastating emotional toll the disease exacts on family members and caregivers of Alzheimer’s patients.

The Alzheimer’s Association projects that by 2050, 959,000 new cases of the disease will surface per year compared with the anticipated number of 615,000 new cases per year anticipated for 2010.

In three years, the first baby boomers will turn 65, the age after which they’ll have the greatest risk of developing AD. By 2050, the Alzheimer’s Association suggests that in the absence of preventive treatment, the number of individuals aged 65 and older with AD could range from 11 million to 16 million. The organization projects that 10 million baby boomers will develop AD—or one of every eight in that generation.

Capricious Incidence
The single greatest risk factor for developing AD is increasing age, with only a small proportion of AD cases being related to genetic origins.

Although AD affects people in different ways, it generally begins with difficulty remembering information. It progresses through various stages during which individuals experience confusion, impaired judgment, inability to organize thought processes, and difficulty expressing themselves.

Advanced stages of AD find people requiring help with the tasks of daily living, including bathing, dressing, eating, and using the bathroom. AD patients eventually fail to recognize loved ones and lose their ability to communicate. Ultimately, the disease is fatal.

A recent study conducted at the Mayo Clinic in Rochester, MN, found that men are 1.6 times more likely to have mild cognitive impairment than women. Mild cognitive impairment appears to increase the risk of developing AD but not every individual who has it develops AD.

Lifestyle factors can influence the risk of developing AD in both men and women, Sam Gandy, MD, PhD, chairman of the medical and scientific advisory council for the Alzheimer’s Association told WebMD.

The Alzheimer’s Association recommends maintaining an active lifestyle that includes mental, physical, and social activities. A brain-healthy diet, low in fat and cholesterol and high in dark vegetables and fruits, also contributes to decreasing the risk of developing AD.

AD Medications
Unfortunately, there is no cure for AD, nor can treatments delay or stop the deterioration of brain cells characteristic of the disease. However, the FDA has approved a small number of drugs that temporarily slow the progression of symptoms. However, Cognex, a first-generation drug that became available in the early 1990s, has created concern due to its potential for causing liver toxicity.

Although medications don’t work the same for all AD patients, some can temporarily improve the quality of life for patients and their caregivers. But for some AD patients, no medication is effective,

AD medications fall into two main categories. One group works better in the earlier stages of the disease while the other is typically prescribed for use in the later stages of the disease.

Cholinesterase inhibitors work best in the early to middle stages of AD. Such drugs prevent the breakdown of the chemical messenger acetylcholine, which is associated with alertness, memory, thought, and judgment. Aricept, Razadyne, and Exelon “increase the ability of brain cells to communicate to optimize their performance,” says Maria C. Carrillo, PhD, director of medical and scientific relations for the Alzheimer’s Association.

The second class, n-methyl-d-aspartate receptor antagonists, has a single drug called Namenda, which is typically used in moderate to severe Alzheimer’s, according to Carrillo. Its mechanism regulates the activity of glutamate, a chemical messenger associated with all brain functions, including learning and memory. It is prescribed on its own or in combination with cholinesterase inhibitors.

And although AD medications can provide a temporary slowing in progression of symptoms, they’re not a panacea. “The reality of these medications is that they don’t work in everyone,” says Carrillo, adding that such drugs are effective in only 60% of Alzheimer’s patients. And, she notes, for those whose symptoms are affected by the medications, those effects wear off over time, possibly as quickly as 12 to 18 months.

Carrillo stresses the need to reevaluate Alzheimer’s patients who take AD medications. Although they may improve cognition, she says, “What they do is delay the worsening of the symptoms.”

Weighing Benefits Against Side Effects
Although she identifies minimal differences among the cholinesterase inhibitors and characterizes the three as “modestly effective,” Ruth Emptage, PharmD, CGP, clinical assistant professor of pharmacy practice at The Ohio State University College of Pharmacy in Columbus, says all three can cause gastrointestinal (GI) upset. Primarily, the side effects include nausea, vomiting, increased bowel movements, and loss of appetite, she says.

In late 2007, Exelon patches, which allow the medication to be absorbed directly through the skin into the blood stream and bypass the entire GI tract, became available, Carrillo says. Clinical trials are underway to test the efficacy of that delivery method for the other drugs as well.

Prescribers base the selection of AD medications on each patient’s unique diagnosis and medical history. For some, the side effects outweigh the benefits of taking the drug. Some patients and their caregivers simply decide AD medications are not for them.

“Side effects themselves are varied,” says Carrillo. “Patients can have side effects to Aricept and not to Razadyne.” Because of the potential for improvement in AD patients’ quality of life, she says it’s important to discuss treatment with a physician to determine what’s best in each case. “It varies so much from one person to another,” she says.

Once medications are prescribed, “Usually patients are started on the initial low dose of one of the medications and titrated up as they tolerate,” says Emptage. “Because the available studies suggest better effect on memory and cognition at the higher doses, patients should be titrated up to these doses unless side effects limit an increase.”

The use of AD medications in combination with other medications warrants particular vigilance, Emptage says. “Because the cholinesterase inhibitors increase acid secretion in the stomach, it is prudent to monitor closely for GI bleeding if taking with NSAIDS [nonsteroidal anti-inflammatories],” she says.
And, she notes, “Any drug, such as the older antihistamine drugs like diphenhydramine that have anticholinergic properties would be antagonizing the effects of these agents.”

Aricept, known to interact with several antiepileptic medications including carbamazepine, phenytoin, and phenobarbital, can also interact with rifampin, according to Emptage. Razadyne interacts with Paxil while Namenda has not been found to have significant drug interactions.

Disappointment on the Testing Front
Results presented at this year’s American Academy of Neurology meeting in Chicago revealed that adding Lipitor, a widely used cholesterol drug, to Aricept showed no significant differences in cognition or global function compared with those taking only Aricept. The 18-month clinical trial included 640 patients with mild to moderate AD.

Researchers had hoped that the class of drugs known as statins would benefit AD patients.

Carrillo admits that the findings resulted in disappointment but says there is “a general feeling that statins can show benefit. There’s a mechanism that extends beyond the cholesterol connection.” She adds that there is  “strong biochemical evidence in the basic biology field that statins may have an effect.” That effect may turn out to be preventive in nature.

Ongoing clinical trials may help answer questions related to the use of statins for AD patients, according to Emptage. “There is certainly epidemiologic evidence suggesting a decrease in the development of Alzheimer’s disease. However, there are no conclusive trials showing benefit in individuals who have already developed dementia,” she explains.

Prospects for Future AD Medications
The future of AD medications focuses on “disease modifying therapies,” says Emptage. Several types of agents are currently being explored. Secretase inhibitors such as gamma-secretase and beta-secretase are being researched as a way to decrease the formation of the neurotoxic beta-amyloid 42 fragment of the amyloid precursor protein, she says.

Another promising compound is Tarenflurbil, which is currently in phase 3 trials, according to Emptage. It works by shifting the cleavage of amyloid precursor protein in less toxic fragments. “It appears this compound may have fewer potential side effects than the early trials with gamma-secretase inhibitors,” she says.

According to a study published online in The Lancet Neurology, patients with mild AD who took 800 milligrams of Tarenflurbil twice daily experienced less decline in functional ability than those who took a placebo in a British phase 2 trial.

Little data exists to accurately predict whether Gammagard could emerge as a significant development in decreasing beta amyloid, Emptage says. Gammagard is immunoglobulin administered intravenously; immunoglobulin contains human antibodies. “It appears the immunoglobulin might to some degree help decrease the circulating beta amyloid protein thought to be involved in the process of neuron degeneration in Alzheimer’s disease,” she says.

Another area of interest lies in antiaggregation agents, Emptage says. “These agents target the already formed beta-amyloid 42 fragment and attempt to increase its clearance from the central nervous system,” she says. Agents included in this class are tramiprosate and O-CLN.

Although a few mood-stabilizing agents such as lithium and valproate are currently under study, Emptage says that little information exists to suggest disease-modifying benefits associated with them. More trial results are forthcoming.

Despite the limited number of drugs currently used in the treatment of AD, the future looks promising, according to Carrillo. She says 10 drugs are currently in phase 3 of FDA approval, with the expectation that they’re only three to five years away from landing in pharmacies.

One of the most significant problems lies in the difficulty of enrolling  enough AD patients in a timely fashion in clinical trials. And, not surprisingly, for phase 1 and 2, she says, “the biggest deterrent is money” for funding.

— Barbara Worthington is associate editor of Aging Well.