Treating Alzheimer Disease: Unmet Needs

Alireza Atri, MD, PhD: One of the major issues in our field in the United States is that there’s a lack of multidisciplinary best clinical practice guidelines, both actually on the evaluation side and also on the care management/treatment side, that look at the care and evaluation of an individual from a multidisciplinary standpoint in multiple practice settings—so primary care, which may be a family practitioner. It may be an MD [doctor of medicine] or a DO [doctor of osteopathic medicine], or maybe be an NP [nurse practitioner] or a PA [physician assistant], or RNs [registered nurses]. In specialty care, it could be neurology, it could be psychiatry, it could be geriatrics. Neuropsychologists, certainly, and other psychologists are in that realm. Occupational therapists, physical therapists, speech therapists fall in that realm and oftentimes are individuals who come across affected patients. And then in subspecialty care, which is someone like me, really a dementia subspecialist.

There are different needs, both for knowledge and proficiency, both on the evaluation side and on the treatment side. The Alzheimer’s Association has convened a working group that I’m involved with, and over the next 6 months we should have a report out on the evaluation side that really looks at best practices that are evidence-based, for an institution medicine sort of process for evidence development and guideline development regarding who the individual is that you’re going to be concerned about.

So this is not screening. This is not going out there and taking and doing tests on 30-year-olds without symptoms. This is really concerning individuals who may have a concern themselves, or a care partner or relative may have a concern, or even the clinician should have a concern based on maybe a constellation of information they have or the clinical profile of the patient. I’ll give you an example. Let’s look at a patient who’s older, who may have managed their diabetes or heart failure or blood pressure well, but now that management is going out of control. They’re having, let’s say, hospitalizations, emergency department visits. They may have out-of-control blood pressure—high, low—or diabetes. That’s a person who, potentially, a clinician could be concerned about.

So the guidelines delineate a pathway really of history, and review of systems and risk factors that should be sort of elicited, and a 3-step diagnostic formulation pathway. And the first one really is: How do we detect it? How do I detect somebody where there may be a potential for something being wrong in the cognitive impairment/dementia spectrum? And that’s through really doing an assessment of the symptoms but also giving a short test of cognition. The second step is defining, delineating what we call the clinical syndrome. Is it memory that’s affected? Is it memory and executive function that’s affected? Delineating that is important because it first actually allows us to help with some of those symptoms, potentially, but it also points toward the potential cause. And third step is: What is the cause of this—the etiology or the contributing factors? And that’s where the biomarkers come in.

So we talk about a tiered approach to testing, where the first tier should be done on everybody. This is relatively broad, with cheap lab panels. These are the things that neurologists and other people, for the most part, do—thyroid function, B12, homocysteine, sedimentation rate, and an imaging study, like an MRI. And then beyond that, if there is still lack of confidence about the diagnosis, there’s a pathway about the biomarkers regarding what to do with the PET scans, spinal fluid, genetic testing, and those things that are relatively new to us. So that’s on the evaluation side.

Beyond that, there really has to be a shared discussion about the goals of the treatment and how you disclose, because that’s a big problem for us in medicine. Patients have symptoms 3 to 4 to 5 years before they see somebody. The workup may take a year or 2, sometimes, in some cases. And then there’s oftentimes not the proper disclosure of what they have, what the prognosis is, and what to do about it. So that’s very, very important.

And then, on the management side, the management side really comes in at 3 different pillars. One is teaching individuals and their care partners about the course of this disease, what to expect, how to manage it through environmental modifications, and support. And then there’s the medication approach. In the medication approach, the first part isn’t to give the Alzheimer medicines. The first approach is to really simplify what they have and take them off of bad medicines. And then, in a stepwise fashion, both give the Alzheimer-specific medications, like cholinesterase inhibitors and memantine, but also treat other symptoms that may emerge. And then, also make sure that lifestyle factors are addressed, and that the care partner is addressed.

So that’s sort of a broad overview. Once we do that, the expectations really aren’t that a patient is going to sit there and their symptoms are going to revert to 5 five years before. A preponderance of evidence suggests that if you do this in a multifactorial perspective, many patients can actually improve a little bit, or be stable within 6 months to a year. But beyond that, the expectation really is decline, and our expectation is to slow down that decline and to preserve and retain independence as much as possible and delay the emergence of behavioral issues, which are very, very difficult to manage.

Ronald C. Petersen, MD, PhD: Right now, there are 4 FDA-approved drugs on the market. They are so-called symptomatic drugs, meaning that they may help with the symptoms, they may stabilize people for a period of time, but they really do not have any impact on the ultimate outcome of the disease.

Now, 3 of these are all in the same pharmacologic class, called cholinesterase inhibitors, and the fourth is a drug called an NMDA receptor antagonist. Again, they work on the chemical systems in the brain, generally do something, but they’re not rocket science when it comes to really having an impact on the disease.

The other class of drugs that is being investigated includes disease modifying therapies. These are drugs that are designed to go after the underlying disease process— again, amyloid, and tau, or maybe other mechanisms—but actually stop the abnormal processing of these proteins such that we can prevent the deterioration of brain function due to the damage caused by these proteins.