What's New in Alzheimer's Disease

How to Preserve Your Brain Function

Dr Fillit is clinical professor of Geriatrics and Medicine and Professor of Neurobiology, Department of Geriatrics, Mount Sinai Medical Center, and Executive Director, Alzheimer’s Drug Discovery Foundation and Institute for the Study of Aging, New York City

Am J Geriatr Pharmacother

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Dr Fillit is the lead author of the new guidelines, “Recommendations for best practices in the treatment of Alzheimer’s disease in managed care” (. 2006; 4[suppl A]:S9-S24), which were discussed last month in (See January 2007). asked Dr Fillit about recent advances in Alzheimer’s disease (AD) and their potential implications for primary care.

What are the latest developments in our understanding of AD?

There has lately been a pretty heavy focus on the amyloid target. But the most exciting thing that is happening now is the increased interest in nonamyloid targets, particularly in therapies that are directed at the neurofibrillary tangles, and how neuronal injury and death occur in association with this disease. One example is the tau molecule. There’s a lot of interest now in understanding the mechanism of tau phosphorylation and tau aggregation and microtubule disassembly, and neuronal death.

Are there new preventive measures that are particularly effective?

Everything that physicians think about in counseling their patients to prevent heart attacks and stroke, they should also think about in terms of preventing cognitive decline with aging. For example, we know now that hypertension, diabetes, and probably elevated cholesterol levels are risk factors for cognitive decline and dementia. So when we counsel patients to take their blood pressure medication, we should be telling them to take it not only because it might prevent a heart attack or a stroke, but also because it might prevent them from losing their mind. The same is true for diabetes.

With regard to lifestyle issues, it has been shown that things such as physical exercise are very important in preventing cognitive decline and promoting cognitive vitality and maybe even preventing dementia. So we should counsel people not to be sedentary and to exercise, not only because is it good for the heart and for preventing stroke, but it’s good for their mind. And people shouldn’t smoke, or drink too much, or get too much head injury. And they should eat a good diet.

There have been a lot of epidemiologic studies published about omega-3 fatty acids, antioxidants, fruits, and vegetables. The same epidemiologic evidence that exists around all those things in relation to heart disease now also exists for AD.

Has there been any progress in the diagnosis of AD?

A primary care doctor can make a diagnosis of AD with about 90% certainty, by following some of these very simple steps:

• Interviewing the patient

• Taking a history of chronic, progressive cognitive impairment

• Performing a simple mental status examination of cognition, such as the Mini Mental-State Examination, perhaps combined with the clock-drawing test

• Ruling out depression as a reversible cause of dementia or of cognitive impairment

• Conducting a medication review to rule out the impact of drugs on cognition in older patients

• Measuring thyroid hormone and vitamin B12 levels

• And probably magnetic resonance imaging (MRI) to rule out tumors and hydrocephalus.

On the horizon are a number of biomarkers that are expected to be available in clinical practice in about 5 years. The closest one to clinical practice is measuring the rate of hippocampal atrophy on MRIs.

People with AD lose about 4% of their hippocampal volume every year, whereas a normally aging person has only about a 0.5% rate of decline. It’s conceivable that serial MRIs, taken over the course of 6 months, would show rapid or significant hippocampal atrophy that would be assessable by the clinical radiologist.

In the absence of obvious signs of decline, is cognitive screening recommended?

I would recommend universal memory screening for patients older than 75 years, about 20% to 25% of whom have some form of dementia, mostly AD. At around age 80, the prevalence is around 40%. At age 65, it’s only about 1%.

In any older patient complaining of memory loss, or if their loved ones or caregivers complain that the patient seems to have memory loss, that patient should certainly be screened. But as a general, population-based approach, the cost-effectiveness for screening probably starts at around age 75.

Since the 3 cholinesterase inhibitors (ChEIs) have been shown to have equal efficacy, how should the physician decide which agent to choose?

The 3 ChEI agents—donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon)—have some differences. I think that the agents that have a once-a-day dosing schedule (ie, donepezil and galantamine) are preferred over agents that are taken twice daily (ie, rivastigmine and memantine).

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In terms of ease of use, that is, getting to a clinically effective dose without having to titrate as well as once-daily dosing, donepezil does all those things. The extended-release formulation of galantamine also offers once-a-day dosing, but it still requires titration to get to a clinically effective dose. However, even though rivastigmine requires dose titration and is taken twice daily, a new rivastigmine patch has just been approved and should become available soon (See , January 2007). So all 3 ChEIs may be getting to the point of having something equivalent to once-a-day dosing.

What is the most important message for primary care physicians in the new guidelines?

The first thing that physicians should know is that the panel clearly endorsed combination therapy for moderate-to-severe AD—with a ChEI plus memantine. Even I was surprised about the strength of the recommendation. But, in fact, the package insert for memantine includes information about the clinical trials being done in a combination therapy setting.

In addition, we recommend therapy across all stages of the disease, except when patients are profoundly ill. We also strongly recommend care management and counseling as an important a component of AD therapy, just as it is for any other chronic disease that we internists manage on a regular basis.

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The new guidelines recommend memantine for mild AD in patients who cannot tolerate a ChEI. Isn’t it unusual for a guideline to advocate an off-label use?

There have been some clinical trials showing positive effects of memantine in mild disease. I guess the sum of all the trials was not impressive enough for regulatory bodies to approve it for this use. Our recommendations, however, are based on the consensus of a panel of experts, based on their experience in the actual practice of medicine. I think our experts clearly felt that patients deserve a chance at therapies that are at least modestly effective in most patients, which is where the off-label recommendation in patients with mild disease who cannot tolerate a ChEI came from. We’ve all seen people with mild disease who got treated with memantine and who responded well. Of course, the number of people who simply cannot tolerate a ChEI is small.