Causes and Detection of Alzheimer Disease

Jeffrey L. Cummings, MD, ScD: Hello, and thank you for joining us for this NeurologyLive™ Peer Exchange titled “Advances in the Treatment of Alzheimer Disease.” Alzheimer disease [AD] is an irreversible progressive brain disorder that slowly destroys memory, thinking skills, and eventually the ability to carry out the simplest task.

Symptoms of Alzheimer disease for most people first appear in their mid-60s. There is currently no cure for Alzheimer, but there are drugs in development that may be promising. In this NeurologyLive™ Peer Exchange discussion, I’m joined by a panel of my colleagues, all experts in the field of Alzheimer disease. Together we’re going to discuss the advances in diagnosis. We’ll review the latest clinical trials and provide practical perspective on how recent data apply to your clinical practice.

I’m Jeffrey Cummings, founding director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada, and research professor at the University of Nevada, Las Vegas. Participating today in our distinguished panel are Dr Alireza Atri, director of Banner Sun Health Research Institute in Sun City, Arizona; Dr Richard Isaacson, director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine in New York, New York; Dr Elaine Peskind, Friends of Alzheimer’s Research Endowed Professor of psychiatry at the University of Washington School of Medicine in Seattle, Washington; and Dr Marwan Sabbagh, director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada. Thank you so much for joining us. Let’s begin.

Well, Richard, I’d like to start with you with our first question. What’s the difference between age-associated memory impairment and Alzheimer disease?

Richard Isaacson, MD: Alzheimer disease is a progressive neurological disorder; it’s a brain disease. It’s a neuropsychiatric disease that involves progressive loss of short-term memory. But it also has other aspects, including changes in sleep, changes in behavior, and problems doing complex tasks. It’s a progressive disorder, and currently we have no cure.

Age-related memory impairment, or age-related cognitive decline, is also sometimes referred to as cognitive aging. And cognitive aging is somewhat the normal or expected changes that happen when someone ages. For example, a word may be on the tip of your tongue, but you may remember it later. Also, it may take you longer to learn something or longer to retrieve something. But those are parts of the normal aging process, and it’s not pathological in the sense of a neurodegenerative dementia, like Alzheimer disease.

Jeffrey L. Cummings, MD, ScD: Very good. And does 1 lead into the other? Does age-associated memory impairment then become Alzheimer disease, or are they really on distinct trajectories?

Richard Isaacson, MD: That’s a great question, and I wish I totally understood the answer. In our program we try to study both cognitive changes and cognitive dysfunction due to pathological aging, like Alzheimer disease, versus nonpathological aging. Different cognitive measures change differently depending on the 2 constructs. Does 1 lead to another? Does 1 make you more predisposed to the other? The jury is out on this, and it’s a little confusing. I think there are some aspects of the pathophysiology that are interrelated, whether it’s vascular comorbidities, metabolic changes, or other things. I think there’s a relation, but I think they’re distinct.

Marwan Sabbagh, MD: Can I add to that, Jeff?

Jeffrey L. Cummings, MD, ScD: Please, Marwan.

Marwan Sabbagh, MD: I was going to say that Richard is right, but we now recognize that people who have age-related cognitive decline, particularly people who complain about their memory—subjective cognitive impairment—oftentimes are predicting changes that could lead to a progressive condition later in the future.

Jeffrey L. Cummings, MD, ScD: So it’s a risk factor maybe without being determinant.

Marwan Sabbagh, MD: If someone is complaining about it, correct. We used to say that they’re worried. Well, now we’re saying that maybe there’s something to pay attention to.

Alireza Atri, MD, PhD: And I would add to that. I agree that nowadays we understand the pathophysiology of these diseases. There are oftentimes proteins that are misfolded, and they start occurring 15 to 20 years before an individual shows symptoms. There’s always this balance between having the disease or these toxic proteins and how much vulnerability or resilience you may have to ward these things off.

Jeffrey L. Cummings, MD, ScD: Very good. Well, let’s go on to our second question. What are the strategies for detecting mild cognitive impairment [MCI] in mild AD? We’re thinking today mostly about mild AD at the early phases of symptomatic disease. Ali, what’s your approach to doing this?

Alireza Atri, MD, PhD: Well, I think timely detection is really critical to improve outcome. I think it’s really important for individuals, if they have a concern, to discuss it with their primary care clinician. Or if there’s a concern from a family member, this should bubble up to the level of a clinician. Also, clinicians can look for warning signs in their patients for this. The strategies would be really to start the conversation and make sure they understand that there is this aging spectrum of changes, but people could have damage that’s occurring, and you’re better off appreciating and detecting it earlier.

Involving family members to get a history about change in symptoms from the patient and a family member, I think that’s a good strategy. Then do a standardized formal review of systems and function. At what level did they function before? How have things changed now? Mood, anxiety, sleep—again, very, very important. Go through an individual’s medications. People get on medicines that are not good for them sometimes. Do that whole pathway, and then ultimately at least do a brief assessment using some of the standardized instruments.

At that point, integrate the information. They may tell you, is something awry? And then, try to understand the nature of it by maybe further testing in some individuals. If you’re unsure, you can refer to a nurse psychologist. And then there are pathways that are multitiered for understanding ideology. So I think, is there a concern? If something is awry, what’s the nature of it? At what level is it mild impairment? Is it actually the dementia level? And then doing other tests to think about etiology. And oftentimes in an older individual, the etiology is maybe multiple, and you can change and affect some of them more than others.

Jeffrey L. Cummings, MD, ScD: Are there specific tests you would recommend or think about?

Richard Isaacson, MD: Yes. To Ali’s point, I would actually routinely order neuropsychological testing on patients with myocardial impairment. I’ve instructed my neuropsychologists to tell me if it’s amnestic or nonamnestic. I really drill down on that because if there’s a heavy amnestic component, I worry about a prodromal Alzheimer pattern. If it’s nonamnestic, I cast the net more widely. Is it MetS [metabolic syndrome], is it depression, or is it prodromal Alzheimer?

Jeffrey L. Cummings, MD, ScD: And it could still be Alzheimer.

Richard Isaacson, MD: It could still be Alzheimer. I actually start with neuropsychological testing in my practice.

Jeffrey L. Cummings, MD, ScD: Neuropsychological testing. Elaine, what’s your approach to the MCI patient?

Elaine R. Peskind, MD: I always think the most important source of information is the family member who knows the patient well: either the spouse or an adult child. Often it’s more likely that a patient with myocardial impairment may have some insight. But once it’s progressing into the realm of Alzheimer dementia, often patients have poor insight. They’re really not aware they have a problem. I’ve heard this referred to as denial, but it’s really that the area of the brain that governs self-awareness is affected early in the course of disease. And patients sometimes just really don’t have a clue. I always think it’s important to have a family member involved in taking the history. It’s more that you examine the patient and you take the history from the family member.

Jeffrey L. Cummings, MD, ScD: I think that’s so critical, and the way I speak with my families about this is I tell them that the patient doesn’t remember that they don’t remember.

Elaine R. Peskind, MD: Right.

Jeffrey L. Cummings, MD, ScD: And that that makes some sense to them.

Elaine R. Peskind, MD: And if you think about it of your own self, if you don’t remember something, you don’t remember that you don’t remember.

Jeffrey L. Cummings, MD, ScD: Yes, exactly, of course. Richard, do you have a standard approach that you use with MCI?

Richard Isaacson, MD: Yes. Taking a detailed clinical history is worth its weight in gold in a situation like this. The clinical pearl that I teach my residents and fellows is, when was the first time you or someone else in the family noticed anything different whatsoever? And oftentimes that really gets someone to think, “Oh, wait. Actually, at the birthday party 3 years ago. That’s when something changed. That’s when something was different.” Really pinning down and getting a detailed clinical history is key. Try to understand: is this a memory problem or is it something else? Could this be a pseudo dementia, doing a depression screen for example? These are some of the really characteristic things.

The other really important part: is there a family history of Alzheimer disease? Just because someone has a family member doesn’t mean they’re going to get Alzheimer disease. But when you have several family members on the chain and they all presented similarly, that really raises one’s suspicion.

Jeffrey L. Cummings, MD, ScD: That’s a really great point. Before we leave this, I want to make the point that doctors have very little time, and we’re talking about taking a careful history here. Are there some key things they should ask? If you had to say, what are the 3 questions they have to ask to understand this? Are there 3 high-yield questions? Ali, what would you prioritize in terms of what doctors should ask about?

Alireza Atri, MD, PhD: I would really prioritize that if you’re going to ask even 2 questions, it would be from the individual and somebody who knows them well. And understanding this change, and not attributing change to anything else: has there been a change or not? And what has been that pace of change? Is it associated with anything else? I think that’s really important.