Sandra, a fit 65-year-old woman, believes in the benefits of proactive health care. She exercises regularly and never misses an annual physical. So when she sees a flier for a free memory screening event at her local Kmart, she thinks it's a great opportunity to check on her brain health too.

Sandra's reasoning may seem intuitive. We check the circulatory, lymphatic and respiratory systems. Why shouldn't we check the organ responsible for their executive function?

This question lies at the heart of a brewing debate fueled by disagreement among Alzheimer's disease (AD) experts, including the nation's leading nonprofit advocacy groups. The debate centers on "memory screening," which uses standardized tests to determine whether a person has normal cognition for his age. Such tests ask people to answer questions and complete simple tasks, such as remembering words and drawing a clock. These screenings, which can take up to 10 minutes, are administered face-to-face at a health fair or a doctor's office.

The controversy about this particular method arises from an urgent need to better manage AD, the fatal neurological disease that robs people of their ability to reason, function and participate in life.

While the disease wreaks havoc in the lives of patients and their families, it also bleeds the health care system, costing more than $100 billion annually, according to the Alzheimer's Foundation of America (AFA). As America's largest population-baby boomers-age and become at risk, experts predict the number of Americans with AD could rise from 5 million today to 16 million by 2050.

"We have to find better ways of treating and taking care of people with AD or we're simply going to be overrun by the epidemic that's already started. That's going to be a disaster, not only for people with AD, but for everyone else, because it's going to wreck our health care system," says William Thies, PhD, vice president of medical and scientific relations for the Alzheimer's Association.

By 2015, Medicare will spend $189 billion on beneficiaries with dementia, and state and federal Medicaid will spend $27 billion on their long-term care, the Alzheimer's Association predicts.

To prepare for the looming epidemic, advocacy groups, researchers and the government have reviewed the role of memory screening. The AFA supports the tool as a way to identify potential patients, who could benefit from early treatment. The Alzheimer's Association does not believe that memory screening leads to earlier detection or treatment intervention.

Both sides agree that people who exhibit cognitive problems should undergo immediate evaluation by a physician. The benefit of screening seemingly asymptomatic individuals is the point of contention.

Benefits of Early Diagnosis
Advocates say that all older adults benefit from memory screening because it detects cognitive problems before memory loss is noticeable.

The AFA began holding an annual national memory screening day five years ago as a way to offer free, confidential memory screenings. More than 2,000 sites, such as community centers and Kmart pharmacies, provide free memory screenings and educational information about AD.

Eric J. Hall, chief executive officer of the AFA, says the foundation is simply trying to promote "awareness, knowledge and empowerment" so people can get the care they need. The AFA stresses that screening is not a diagnosis.

"Memory screenings are the first baby step on the way to diagnosis, which may not be diagnosis of AD at all," he says. The tool can help identify people with reversible memory problems, such as a B12 deficiency or thyroid imbalances.

Critics agree that memory screening would be beneficial if it culminated in early diagnosis. But they say it's incorrect to assume that memory screening actually leads to earlier diagnosis and treatment. Inaccurate tests and lack of follow-up foil the process, they say.

Studies show that factors such as age, ethnicity and education can decrease the accuracy of commonly used screening tests. Mass screenings, such as those administered at national memory screening days, produce more inaccurate results because the environment can be distracting, critics say.

In recent years, physicians have successfully diagnosed AD patients by performing a battery of tests. However, John Trojanowski, MD, PhD, director of the Alzheimer's Disease Center at the University of Pennsylvania, says this process may take multiple visits over the course of two to three years.

One in 10 diagnoses is still incorrect, Dr. Trojanowski estimates, even after physicians conduct these extensive physical, neurological, psychological and mental exams. He dismisses 10-minute memory screening exams as useless.

Advocates say that memory screenings are valuable, even if they sometimes produce inaccurate results. Paul Solomon, PhD, is a neuroscience expert at Williams College and a member of the Alzheimer's Disease Screening Discussion Group, which recommends routine screening. He compares memory screening to other screening techniques, such as mammograms for breast cancer.

Dr. Solomon says many mammograms show false positives. Although an abnormal mammogram calls for a full diagnostic evaluation, it doesn't mean a woman has breast cancer. But if she does, the subsequent evaluation can lead to early diagnosis, which provides the best opportunity for effective treatment.

However, unlike mammograms, many patients who receive poor scores at mass screenings do not follow up with their physicians. Patients who do find little infrastructure to handle positive memory screening results.

"If you screen people and they take the report to their physician, what is he going to do with that?" asks Charles Smith, MD, a neurologist at the University of Kentucky Sanders-Brown Center on Aging and leader of a study on a new AD screening device, Cognision. "The assumption is that there's this huge system in place to do something with the information that people have obtained at Kmart." The medical community simply is not equipped to process the results of mass memory screenings, he says.

Even when a memory screening is conducted in a doctor's office, poor results do not necessarily lead to treatment. A recent article in the Wall Street Journal cites a study in the Journal of General Internal Medicine by Soo Borson, professor and dementia specialist at the University of Washington. Of 524 adults screened in a doctor's office, only one in five who exhibited memory problems was referred to a specialist or received a diagnosis or prescription for medication, the study found. Lack of time may be one reason for so little physician follow-up, Borson suggests.

John Wesson Ashford Jr., MD, PhD, agrees. "The typical story is that the doctors are busy and overworked," says the senior research scientist at the Stanford/VA Agig Clinical Research Center and chair of the memory screening advisory board for the AFA. "[Doctors] ask their patients if they have any problems, and the first thing people forget is that they have a memory problem. That might seem funny, but unfortunately, it's reality. Doctors mostly don't have time to deal with the issue."

However, Dr. Ashford says physicians would be more likely to recommend further evaluation if patients presented their abnormal memory screen results from events such as the National Memory Screening Day. He believes the day educates patients and empowers them to begin a dialogue with their physicians.

Treatment Options
Both sides agree that patient education is important because many people don't realize treatment is available.

Four FDA-approved drugs treat the symptoms of AD. Razadyne (galantamine, previously known as Reminyl), Exelon(rivastigmine) and Aricept(donepezil) are a class of medications called cholinesterase inhibitors, which are approved to treat mild to moderate AD. Namenda (memantine) is an N-methyl D-aspartate antagonist, approved to treat moderate to severe AD.

Advocates say it's important to screen people before they exhibit symptoms because AD medicines are most effective when taken early in the disease. However, some critics say it's not helpful to identify people before they exhibit noticeable memory problems because medication is useful only in those with clear symptoms.

Disagreement also exists about the benefits of AD medications because they cannot change the disease's outcome. "If there was treatment for AD, I'd recommend screening, but there is no disease-modifying therapy," says Dr. Trojanowski.

The AFA says treatment does not have to improve the condition to be helpful. There is no "silver bullet," says Hall. Instead, medications slow the progression of symptoms.

However, some debate the drugs' ability to meaningfully improve quality of life for a substantial length of time, including the United States Preventive Services Task Force (USPSTF), a federally funded, independent panel of experts. The USPSTF, which doesn't support or reject memory screening, believes medication offers limited benefits. The drugs do not help people remain independent, the USPSTF states.

However, Dr. Ashford believes medications can have a significant impact on patients and their families by improving their quality of life for six months to two years. "That's worth a lot," he says. "Before these medications were available, I saw so many patients who were just impossible to manage and whose families were suffering. If you can get them on medication, all of a sudden, everyone's doing a lot better," he says.

Both sides agree that a healthy lifestyle can help prevent the onset of AD. Dr. Trojanowski "passionately recommends" exercise, cognitive stimulation, social networking, maintaining a low BMI and blood pressure, and diet and exercise for everyone, whether or not they perform well on a memory test.

Advocates say memory screening can motivate people to adopt these healthy lifestyle practices. Dr. Ashford compares an abnormal memory screen with a high blood pressure reading. Although people are aware they should exercise and watch their diet, many do not do so until they find out their blood pressure is elevated. In the same way, an abnormal memory screening can prompt people to take fish oil supplements or do brain exercises, such as crossword puzzles.

The concept of memory screening as a motivator extends to other important issues as well. Many families must make important decisions for their loved ones who have succumbed to the disease. Advocates of memory screening say an abnormal result leading to early diagnosis gives patients time to plan for their care, decide on future living arrangements and set their financial affairs in order while they're still lucid. An early diagnosis also can help families prepare emotionally and alert them to monitor patients' medications and driving.

True Value of Screenings
It's difficult to objectively evaluate the overall medical, financial and social effects of memory screening because no large-scale, long-term studies on the practice exist.

Dr. Trojanowski says resources from the already-underfunded field should not be allotted for memory screening without hard data showing that it ultimately improves an AD patient's experience.

Dr. Ashford believes that sufficient information supports the "cost-worthiness" of memory screening, citing 200 tests for dementia. He has analyzed the evidence of the disease, the benefits of a true positive, the harms of a false negative and the cost of the assessment. He concluded that annual memory screening is beneficial for everyone over 75, and for people over 65 with a family history or other risk factors.

Looking Toward the Future
A recent report by the Alzheimer's Association predicts that 10 million baby boomers will develop AD in their lifetimes. Dr. Solomon expresses the pressing need for stronger action against the disease's onslaught.

"What we're doing now is not working. Half of the people with this disease are not diagnosed, and three quarters of them are not treated. This problem is going to magnify when the number of people with this disease increases three-, four- or five-fold over the next 50 or 60 years. I'm not sure we have the luxury to wait," he says.

Physicians can take immediate action against the surge by speaking with their patients about AD. Advocates and critics of memory screening agree this communication is crucial, but disagree over the best means to achieve it.

The AFA encourages routine memory screening in primary care, in addition to National Memory Screening Day. The Foundation supports a proposal to add a memory screening test to the "Welcome to Medicare" physical, the initial exam for Medicare Part B, to record a baseline score for everyone enrolled.

Rather than a mandated, standardized exam, the Alzheimer's Association promotes "cognitive surveillance" by patients and physicians. Thies says the structure of conversations between physicians and patients can be "highly variable and adjusted to the needs of particular practices and patients."

Ideally, the debate over memory screening will become irrelevant when disease-modifying drugs and vaccines are developed. Dr. Smith is optimistic about drug research, in particular a new class of medications in trial, selective amyloid lowering agents.

But a medical breakthrough may not come in time to save the current health care system.

George J. Isham, MD, MS, a member of the USPSTF, recognizes the need to address this "devastating" and "compelling" situation, but says that passion for the cause should not preclude systematic evaluation. "People are very concerned about this condition and want to do everything possible for it, regardless of effectiveness."

Until memory screenings are proven effective, the decision to use them rests with people like Sandra and physicians like you.

Nicole Woods is assistant editor. She can be reached at nwoods@merion.com.

Drugs on the Horizon
Every 71 seconds, an American develops Alzheimer's disease, cites the Alzheimer's Association. Pharmaceutical companies are racing to develop more effective medications to stem the tide of this epidemic.

The following medications in clinical trials have otential to become AD's next blockbuster drugs.

Name: Flurizan

Generic/alternative names: MPC-7869, r-flurbiprofen, tarenflurbil

Mechanism of action: Selective amyloid-lowering agent

Role in AD: This medication has disease-modifying potential in patients with mild AD because it lowers levels of AB, a main component of plaques. It is referred to as "selective" because it regulates y-secretase activity to lessen production of AB, without preventing its other functions. In the Phase II study, patients taking 800 mg daily demonstrated significant positive effects in cognitive and functioning tests. After two years, symptoms remained stable or improved in a meaningful portion of patients.

FDA testing: Phase III testing

Name: AAB-001

Generic/alternative names: Bapineuzumab

Mechanism of action: Humanized monoclonal anti-AB antibody

Role in AD: In 2002, trials for AN-1792, an "Alzheimer's vaccine" against AB, were halted when 6 percent of vaccinated subjects experienced encephalitis. But the vaccine lowered plaque levels. Scientists hope AAB-001 will have the same AB-lowering ability without the adverse effects because it is a passive immunotherapy approach. Instead of inciting the patient's immune system to produce anti-AB antibodies, as AN-1792 did, AAB-001 provides ready-made antibodies.

FDA testing: Positive results from Phase I and midpoint data from Phase II prompted the launch of Phase III testing before Phase II was completed.

Name: Dimebon

Generic/alternative names: Dimebolin; 3,6-dimethyl-9-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-y-carboline dihydrochloride

Mechanism of action: Cholinesterase and NMDA receptor inhibitor

Role in AD: Dimebon was originally categorized as an antagonist to H1-histamine receptor and has been used as an antihistamine in Russia since 1983. It prevents neuronal death by reducing mitochondrial swelling. In a recent clinical trial in Russia, patients receiving Dimebon showed statistically significant improvement in five different cognitive tests; patients receiving placebo deteriorated in the same five exams.

FDA testing: The manufacturer is using FDA-approved formulations of the drug to validate previous studies from the former Soviet Union. Its Phase II testing shows promising results.

Name: LY450139

Generic/alternative names: hydroxylvaleryl monobenzocaprolactam

Mechanism of action: inhibits y-secretase, reducing beta amyloid

Role in AD: Instead of testing cognitive or functioning capabilities, LY450139 measures blood levels of AB as a biomarker for AD. In a trial, levels in the fluid bathing the brain, the cerebrospinal fluid, did not decrease. Phase II clinical trials showed impressive decreases in blood A?40 plasma levels-from 58 percent to 65 percent-in patients taking 100 mg and 140 mg doses. However, other studies showed that AB levels later rose beyond baseline after an initial dip. In all clinical trials, subjects experienced some adverse effects, most notably gastrointestinal problems with increased white blood cell count. Gamma secretase has important functions critical for normal bodily health. Inhibiting it to reduce amyloid in AD without causing significant side effects may prove difficult.

FDA testing: Phase II results were significant enough to warrant Phase III testing, which began in March.

Information excerpted from the Alzheimer Research Forum, Drugs in Clinical Trials, www.alzforum.org.

Better to Know?
Does genetic testing for the APoE gene empower patients or simply waste their money?

More than 50 years after helping discover the structure of DNA, James D. Watson, PhD, became one of only two people to have his full genome decoded. He published his entire sequence for research purposes-with one exception. Dr. Watson requested the omission of his APoE gene, an indicator for Alzheimer's disease (AD). He said he didn't want to know his risk unless he could "do something about it."¹In contrast, J. Craig Venter, PhD, Dr. Watson's rival, and the only other person with a fully decoded genome, left his APoE information in his published sequence. It reveals that he carries APoE e4, the variant that predisposes a person to AD. "How could one not want to know about one's own genome?" he asked.²

These conflicting views from two of the greatest minds in the field encapsulate the debate about the value of testing for APoE in the general public. Many issues raised by both sides are the same as reasons for and against memory screening. However, genetic testing for APoE is even more controversial because it tests people years-or even decades-before they could experience AD symptoms. In addition, APoE is only a risk factor for AD, not a definite biomarker.

Although a test for APoE has been available for almost 15 years, it was used for research purposes only. That changed in March 2008 when a private company, Smart Genetics, began offering the test directly to consumers for $399. Customers receive a kit with a container for saliva for testing, and access to education, genetic counseling and support services.

Many physicians believe APoE testing should remain in the realm of research because it doesn't provide consumers with adequate information. John Trojanowski, MD, PhD, director of the Alzheimer's Disease Center at the University of Pennsylvania, says direct-to-consumer APoE testing has little value because there's no "pregnancy test equivalent" for AD.

The indirect relationship between APoE and AD is not the only limitation of the test. Lack of preventive treatment for AD is another reason researchers don't reveal APoE status to study subjects.

Julian Awad, CEO and co-founder of Smart Genetics, says people can use genetic testing information for financial planning, creating a living will or making healthy lifestyle changes to delay the disease's onset.

Although everyone can benefit from these proactive measures, Awad says the testing process motivates people to implement them. He cites the Risk Evaluation and Education for Alzheimer's Disease (REVEAL) study,³which found that participants who learned they had APoE e4 were more likely to make positive health behavior changes.

Media coverage on Smart Genetics may lead patients to ask for your advice about APoE testing. Whether APoE knowledge will benefit a patient probably depends on whether he has a more proactive or reactive personality, as evidenced by Venter and Watson's different reactions to APoE testing. With no expert consensus, it's your patient's personal choice as to whether APoE information is worth the price.

-Nicole Woods

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