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Cognitive Check: A New Vital Sign? Advancing Cognitive Health Assessments in Primary Care

Introduction

Speaker:  The title is Cognitive Check: A New Vital Sign? Advancing Cognitive Health Assessments in Primary Care.

Content Director & Presenting Faculty

Dr Pierre Tariot: Who am I? I'm an internist and geriatric psychiatrist. I've spent my career focused on the care and study of people with or at risk for diseases like Alzheimer's disease. I've also spent a lot of time working with our primary care system to try to help our primary care clinics and providers feel more comfortable evaluating people with or at risk for suspected cognitive impairment. So it's something near and dear to my heart.

Here are my disclosures. Oh, by the way, I'm at the Banner Alzheimer's Institute in Phoenix, where we provide care and do a lot of clinical research. Here are my disclosures. They're all around pipeline review, drug selection, drug testing. I don't have any commercial relationships with any companies. Our sponsor today is Lilly. I have no financial relationships with Lilly.

Learning Objectives

So I won't read every word of these, but the learning objectives are to apply evidence informed strategies, including:

• The information about these new blood-based biomarkers to support early detection and assessment of cognitive impairment or suspected cognitive impairment in your aging patients;
• To initiate compassionate, informed, patient-centered conversation about cognitive health in your patients during routine visits and chronic disease management visits. Bearing in mind age-related concerns; and lastly
• Design a patient-specific management plan to address modifiable risk factors for cognitive decline during these visits, factoring in age, lifestyle, medical issues, and psychosocial factors.

The Coming Dementia Pandemic

So let me get into this and remind – well, I'll mention that I'm a part of a group that developed this material. So I'm speaking on behalf of several people, but we're eager to get your feedback about whether this resonates with you. So, the good people, for instance, at the Alzheimer's Association tell us that we're facing a pandemic of dementia. Now about 7 million Americans living with Alzheimer's and related disorders. We're going to hit a little under 14 million by 2016, a doubling of the 2020 prevalence figures. The reality is that our healthcare system writ large is not prepared for this. We don't have enough specialists. We don't have the technical infrastructure. And frankly, we haven't prepared our own colleagues who specialize in primary care general medicine to handle this type of work. And we haven't factored in the need to provide care for our carers, who have a high risk of medical complications and major depression that they wouldn't have experienced otherwise.

The graph on the right just makes a couple points. The numbers are increasing, as I mentioned, and the numbers are increasing, especially in older Americans and age, as we will learn more about it in a minute, as a major risk factor for late-onset Alzheimer's disease. So the numbers of people with Alzheimer's and related conditions are going to skyrocket.

What Does the AD Population Look Like?

What does the Alzheimer's population look like? And I'm going to elaborate on this a little bit later. But on the left is the graph saying that basically in younger people there were a couple of takeaways here. The big picture is the younger somebody is with Alzheimer's disease, the more likely they are to have the mild cognitive impairment stage of the disease. And then in the older ages, the more likely they are to have frank dementia. That's mostly what's packed into the graph. And then the data on the right simply make the point that at least in 2020, more women were affected than men for complex reasons.

Typical Course of Dementia

This is a particularly important slide. Let's say it's a slide of my memory and thinking ability over years, knowing that I'm destined to develop Alzheimer's dementia. So this is really a very basic but important slide.

I will go through a period, and pardon my lousy graphics. There shouldn't be an uptick there. But anyway, there will be a period of normal memory and thinking where nothing will be wrong, nothing evident at all. Then I will enter a phase that I won't be aware of [inaudible] patients clinically, but the disease process is ticking away. We call that the preclinical stage of Alzheimer's disease. And remarkably, that can be 10 or 20 years. And remarkably, to get ahead of my ski tips. , we have the ability to detect that, those brain changes despite the fact that I don't have clinical symptoms yet. So that's at least a research opportunity that we'll come back to later. So that's normal memory and thinking with or without brain biological changes of Alzheimer's. If those changes are there, we call it preclinical or perhaps premanifest Alzheimer's disease. Then I will ease into this phase called mild cognitive impairment. And forgive me for level setting if you know this already, but this affects something like 10 million Americans.

There are three criteria of concern. I'm concerned, my wife, Laura, is concerned, more likely, or you, my medical provider, are concerned something's changed. I'm not the same. So, concern. Second criterion, objective cognitive impairment compared to age and age-matched controls or peers, even including office testing. That doesn't need to be fancy testing. And number three, my functional status is largely intact. Then I will ease into the dementia phase of the illness, where there are obvious impairments in memory and other thinking ability getting worse over time. Obvious functional impairment to the point where I'll eventually become dependent even in basic activities of living.

So that's the ski slope that I'm on. We're going to talk about really all of these phases.

Not All Dementia Is AD

Just a pointer that complicates things. Remember that if I come to you with frank dementia already, and not all dementia is due to Alzheimer's disease, right? So the pie chart on the right makes the point. It could be Alzheimer's, which does account for the majority of the dementia presentations, either by itself or comorbid with other conditions. Vascular, Lewy body, that sort of halfway between Parkinson's and Alzheimer's, the frontotemporal dementias, the quote, other slice of the pie, things like Parkinson's, and so forth.

So not all dementia is due to Alzheimer's, although the lion's share is number one. Number two, the older you are, the more likely you are to have mixed pathology. So pro tip, if your new patient in the waiting room is, let's just say, 85, you know that number one, she has close to a 50/50 chance of having a dementia. And number two, if she does, there's a 30-50% chance that it might be due to multiple conditions.

Assessing Risk Factors for Dementia

Okay. If you can figure out this abstract graphic, you're a smarter person than I am. But anyway, let's go to risk factors because this is really cool information.

Patient Case: Carlos

Carlos is going to be our case throughout this presentation to try to anchor you to a real person. He's very handsome, by the way. 53 years old. Works in tech. Married. He's got two adult children. He married young. You've followed him for 15 years. He's okay at his annual visit with you. He mentions that his mother has Alzheimer's dementia. Things are getting tough. He's worried about whether she has to get residential care or they need in-home care. And it's not easy for him to be in this role, and he doesn't want his own family to deal with him if he's going to get dementia in the same way that he doesn't want his family to be burdened. He says, "Hey, what can I do to reduce my risk of dementia or plan ahead? Am I eligible for FDA-approved treatments? Am I, Carlos, eligible and/or am I eligible for treatment or other research?"

[00:17:38]

Time for Reflections: How Would You Respond to Carlos?

So what I want to do is help you answer Carlos's questions if you don't know the answers already.

Nonmodifiable Risk Factors for AD: Age, Sex, and Genetics

Okay, so we're going to break this into two easy parts. What are Carlos's non-modifiable risk factors: his age, his sex, and his genetic background. So graph on the left. Hugely important. Age is a big risk factor for the typical form of late-onset Alzheimer's disease. I'm not talking about the genetic form of Alzheimer's disease that occurs kind of in the 50s. If somebody is between 65 and 74, and that's all you know about them. They've got about a 5% chance of having Alzheimer's disease. 75-84 that about triples. 85-plus, you're talking in the one-third to 40% range-ish. So age, a huge risk factor. Can't modify that. Carlos is below 65. So, statistically, his risk of having disease now is low. Certainly, manifest disease

Over to the right, upper-right, genetics. The major genetic risk factor is carriage of one or more variants of a gene coding for a protein that you may have heard of called apolipoprotein E, talked about a lot in cardiology and neurology. There are several variants of the APOE gene and protein. The one called APOE4 confers increased risk of Alzheimer's disease and occurring at a younger age. So if you're a noncarrier, call it 5-ish percent. You're at heterozygote, meaning you carry one copy. Your risk about triples. If you carry two copies, your risk goes up as high as 30-40%. So, that's genetics. And then, of course, I will repeat the point, lower-right, that women are more susceptible than men.

So Carlos, he may have a family history, but we don't know his genetics. Remember, his mom has been diagnosed clinically with Alzheimer's disease.

Cumulative Impact of Modifiable Risk Factors for Dementia

Okay. Now, hugely important slide. Let me set the context. There's an international group of experts convened by Lancet called the Lancet Commission on Modifiable Risk Factors for Dementia, and they published this major review every few years. The most recent one came out about 18 months ago, and it's on the cumulative impact of modifiable risk factors for the development of dementia in the future. Let me unpack it for you because it's really cool and very important.

The graphics, the left-hand of the graphic, the takeaway is, as much as 45% of future dementia risk for Carlos is due to modifiable factors. Okay, then the column to the right, it refers to those modifiable factors. The percentages basically refer to ,if you eradicated that risk factor, how many cases of future dementia you would eliminate. So these are hypothetical numbers. This is also known as the population attributable fraction.

I won't read all of these. You can look at yourself, but just look at hearing loss, for example, 7%. In theory, 7% of future dementia risk could be obliterated if we eliminated hearing loss. That's incredible. Look at high LDL cholesterol. That was one of the pretest questions. 7% at risk. Keep going down. Hypertension 2%. 2% looks like a small number, but if you look at the fact that - that between, let's just say, 130-200 million people in the world are going to develop dementia, 2% prevention of that is actually a very big number.

So these factors on the right, the lifestyle factors that we can keep people on. As an example, look at this list. I'm sure you're not going to be surprised. Oh, I know about this. A lot of this is relevant, for instance, to heart disease as well. Maybe even cancer. So you're familiar with these, but you may not have known that they apply to future dementia risk.

Impact of Vascular Health on Dementia Prevention

Now I just have a handful of slides giving you examples of some of the prior or ongoing work that's buttressing these claims. So on the left, the very important SPRINT-MIND trial. This was published a few years ago. SPRINT was this amazing study done by our Heart Health colleagues who a few years ago said, let's take people with hypertension. Let's do an open-label trial where they're randomized to standard-of-care, which is below 140 systolic. Systolic is the emphasis, not diastolic. We'll randomize them to standard-of-care target systolic to assertive treatment of 120 systolic or below. Okay. That was the SPRINT trial that was stopped early because of overwhelming benefit on death, heart attack, stroke, all kinds of the kidney disease, retinal disease, you name it. The SPRINT-MIND sub study almost 10,000 people looked at cognitive outcomes and found, bottom line, about a 15% reduced incidence of new cognitive impairment or dementia.

So these are people, average age, about 70. This was, you know, time-limited therapy, and yet just manipulating systolic blood pressure, reduced new-onset cognitive impairment or dementia. Boom. Very important outcome.

To the right, ongoing trial just wants you to be aware of it. It's not on any quiz. The largest ever dementia-related trial is called PREVENTABLE, NIH-funded. 2,000 people 75 and older without significant heart disease who haven't been on a statin, randomized to a statin, atorvastatin in this case, or a placebo, and the primary outcome is prevention of dementia or obvious functional decline.

Diet Can Influence Cognitive Decline and AD Pathology

This slide, basically all about diet. I know you're only eating steel-cut oatmeal right now or, you know, very healthy, not too sweet granola with a little yoghurt, whatever. The box to the left summarizes what a healthy diet looks like in the eyes of these diet experts. I won't go through all of it. The unhealthy groups, I know you're not eating sticky muffins, you know, cinnamon bun, whatever, butter with a lot of toast. So that's what healthy and unhealthy diets look like.

Two graphs to the right. The upper graph shows that according to how much an older person stuck with a healthy diet over a period of up to 10 years of follow-up, they showed less cognitive decline than people who had intermediate or low adherence to a healthy diet, lower right, and that was associated with a lot less Alzheimer's pathology at autopsy.

So, your diet equals your brain health. Pretty simple.

US POINTER: Multidomain Lifestyle Modification

Here's an example of a recent publication on the so-called US POINTER study. There's a lot in here, but I'm going to just simplify it in the interest of time.

A couple of thousand sedentary older Americans, 60-79, cognitively unimpaired at baseline. Lower right, they were treated with a package, a toolbox of aerobic exercise, healthy diet, cognitive stimulation, and various degrees of coaching. The coaching was either pretty intensive or really sort of self-directed.

Upper graph to the right, the takeaway, this is a cognitive score vs the two years of follow up. The good news is cognitive performance improved, and that improved in both groups. The red group, which is the intensive coaching group, and the blue group, the self-guided intervention group. Both groups improved. This stuff worked. Yes, the intensive coaching group worked a bit better. But perhaps the headline is everybody who did this showed cognitive benefit over two years. It can help. This stuff helps. You know, it's - it conforms with The Lancet Commission.

Association of Sleep Disorders With Dementia

Now, the Lancet, so, one last example. And this wasn't in The Lancet Commission report, but I feel we must talk about it because, as you probably know, those of you who practice, sleep has such a huge impact on health, including brain health. So as I age, it is normal for me to have a change in my sleep, mostly a chance of awakening during the night before I go back to my so-called second sleep.

But poor quality of sleep is not normal, and particularly increased sleep latency or decreased duration. And of course, these things not only contribute to dementia, but other health conditions and other health conditions contribute to sleep disturbance.

So maybe the takeaway here is that we treat sleep like medication, and these sleep hygiene principles are just so important. And I'll just hit some of the highlights:

• Stay on a regular schedule;
• Make sure your bedroom is really for sleep;
• Don't use it as an office
• Try not to watch TV;
• Try to get regular exercise;
• When you go to bed, you know, make sure it's dark. Cool is a big factor; and
• Be sure you get plenty of light during the day.

So just some basic precepts.

Optimizing Cognitive Health in Early Life

So what we're trying to convey to you is that talking about brain health is something we can do across the lifespan. And for those of you, I bet there are no pediatricians in the room or in the in the virtual audience, but pediatricians talk about brain health from the very beginning: diet, activity, sleep, dental care, so important to brain health, eye care, injury prevention, right? Pediatricians do it. Let's all do this. Let's do this across the lifespan.

How Can We Help Carlos Optimize His Cognitive Health and Reduce His Risk of Dementia?

So back to Carlos. Let's dig into some of his details. You know, he's 53. You know about his mom, but you didn't know his father died at a young age of stroke with a lot of cardiovascular risk factors. His BMI is 30. That's not good. His blood pressure is 135/85. I would submit to you that that is not acceptable. His one - hemoglobin A1C is 6. Not good. Not good enough. He's on atorvastatin, but his LDL is still elevated at 90. He doesn't go to the gym. He walks his dog a couple of times a day.

The more you talk to him, the more you realize he does eat junk food during the week. He didn't smoke, thankfully. He has booze maybe five evenings a week. He gets six to seven hours of sleep, but his wife mentions in passing that he snores.

Time for Reflection: How Can We Help Carlos Optimize His Cognitive Health and Reduce His Risk of Dementia?

So by now, you can sort of cotton on to the things that we can talk about with him, right? He's got family history. BMI is up, blood pressure is high, cholesterol C is too high. He's not getting much exercise. His diet isn't optimal. You know, he's not drinking a lot of alcohol. But maybe he doesn't know that no amount of alcohol is good for his brain. And maybe, maybe, maybe we'll look into his sleep in more detail.

Windows for Amyloid-Targeted Therapies in AD

Okay. One of Carlos's questions was whether he's eligible for FDA-approved treatments to prevent future cognitive impairment or dementia, particularly due to Alzheimer's. The answer is no, but here are the details.

AD Pathophysiology Begins Decades Before Symptoms

So I showed you my ski slope curve, right? So in the blue arrow here, I go through my cognitively normal phase. I ease into the mild cognitive impairment phase. I ease into dementia phase. In the cognitively normal phase, I don't know it, but there are biological changes in my brain that can be detected with biomarkers. But I don't know this yet. Later, as I develop mild cognitive impairment, there may be some structural changes. Then I develop symptoms, and that's when the typical diagnosis occurs. Early intervention can occur in theory. Well, not in theory. In practice, in the cognitively normal phase of my condition all the way through mild cognitive impairment and early dementia due to Alzheimer's. So those are the opportunities for intervention.

Pre-symptomatic the opportunities are these lifestyle variables. Symptomatically, there are two FDA-approved treatments for the pathology due to beta amyloid aggregation outside of cells in the brain, which is one of the key pathological hallmarks of Alzheimer's disease. And we can actually remove that bad-boy protein with currently available antibodies against beta amyloid.

2 FDA-Approved Antiamyloid Monoclonal Antibodies for Treatment of AD

So, Carlos is not eligible for these because he doesn't have symptoms. But here they are. There are two of these antiamyloid monoclonal antibodies. You have to have symptoms, either mild cognitive impairment level, which we defined before, or mild dementia. You have to have elevated brain amyloid on an appropriate test, which is usually a PET scan, or less commonly, spinal fluid testing. We'll get to the blood test in a moment.

The two drugs are called lecanemab and donanemab. MAB, meaning monoclonal antibody, both entail, at this point anyway, intravenous infusions. In the case of lecanemab, it's every other week for 18 months, followed by a maintenance phase, which could be less intensive IV, or now, recently approved sub-Q therapy. Donanemab monthly infusions can be stopped once amyloid has cleared. And in both cases, of course, the treating physician is going to monitor how the patient is doing in terms of cognition and function. Okay. So these are available for people with MCI, mild cognitive impairment, or mild dementia due to Alzheimer's disease.

Rationale for Clinical Trials for AD Prevention

What about clinical trials? Well, that's a different question. Carlos may or may not be eligible. The devil is in the details. We have launched six international – we, at my institute in Phoenix, have launched six international Alzheimer's prevention trial. How come this urgency? Well, I mean, it's a huge unmet need. We know that these silent brain changes are occurring. We know that we can detect those brain changes with biomarkers. We've got plausible therapies. You know, will early intervention help? You may not know that nine prevention trials were launched and completed in the last decade. Most of them were negative, but they did tee up the current portfolio of several prevention trials for Alzheimer's disease that are going on.

Current Clinical Trials for Prevention of Symptomatic AD

Now, don't worry, this won't be on the quiz. This is just sort of a graphic for me to make the point that – a couple of points there are multiple prevention trials. They're all active. Many of them are using anti-amyloid therapies. A couple of them are using anti-tau. I didn't get into that bad-boy protein, but that's another one of them that's a key player in Alzheimer's disease, the T-A-U, tau protein. Some of them target tau alone or plus-minus the anti-amyloid therapy.

You see the age ranges here? Actually, they don't fit for Carlos. He's a little bit too young. Many of the primary endpoints, the second to last column, are clinical outcomes. And you see that these are all ongoing. And remember that PREVENTABLE is also a prevention trial. He's not eligible because the lowest age for that is 75.

I'll tell you how Carlos can learn about prevention trials because they're more coming a little bit later.

Should Carlos See a Specialist?

So, should Carlos see a specialist? We hope you say no. Here's why.

PCPs Can Provide Care for Unimpaired Individuals With Cognitive Concerns

If you put all the specialists in the United States together, dementia cognitive specialists, we couldn't take care of more than 10% of people with cognitive impairment or dementia, let alone the millions of people at risk. And the Rand Corporation did a study of US preparedness for dealing with dementia and concluded, you know, the average wait time for a new patient visit is 18 months. In the Mountain West, it's up to five – and rural Southeast – it's up to five years. There just aren't enough specialists. And that's why, for instance, lower-left, the European Task Force said that these memory clinics are not really well suited to take care of people who are unimpaired and at risk. Let's help our colleagues who specialize in primary care feel more comfortable doing that.

And on the right, the American Academy of Neurology made a similar point. Those of us in primary care, and I used to be myself, you know, have these long-term relationships where we're used to managing chronic disease. We're used to monitoring things. We're used to intervening and screening, and so let's work together to figure out how primary care can do more of this kind of work.

How to Talk About Brain Health With Patients in Primary Care Settings

And if we're going to do that, how do we talk about it?

Public Interest in Dementia Prevention Is High and Increasing as the Population Ages

Well, here's an introductory slide on the talk part. Your patients are being bombarded with information about decreasing dementia risk, improving cognitive performance. You know, the details here don't matter. New York Times, 10 Ways to Keep Your Mind Healthy in 2025. The lower-right, warding off dementia: more reading, praying, and listening to music. You know, people are hearing this type of thing.

54% Would Want to Know if They Had MCI Due to AD - Alzheimer’s Association Survey

And actually, the Alzheimer's Association did a very interesting US population-based survey in adults in the United States. First question I'll talk about, if you had mild cognitive impairment due to Alzheimer's disease, would you want to know? And more – a little more than half said yes. And the reasons I, you know, don't read all of these details, but I could plan for my future. Maybe I could get access to early treatment. Maybe I could start taking other measures to improve my brain health outcome.

And so, to the right here, a few takeaways. People were more likely to want to do legal and financial planning and healthcare planning, more likely to think about their residence, and likely to want to learn about whether they had access to so-called DMTs, disease-modifying therapies.

Only 40% Would Talk to Their Doctor About Symptoms Right Away - Alzheimer’s Association Survey

But the sort of not-so-good news is if you had symptoms, but there were, that's all you knew. Only 40% would bring it up with their healthcare provider. It would – the diagnosis would be difficult for me to accept. Treatments limited doesn't really work. I'd be ostracized. And this perceived barrier was magnified in Black and Hispanic Americans compared to White Americans, and Black, Hispanic, and Asian Americans were twice as likely to say, "I don't have access to care, so what's the point of bringing it up?" So this is a problem that we can all share and try to improve as a society.

4 Key Themes in Barriers to Conversations About Cognitive Concerns

So, you know, in a nutshell, the themes on the left, primary care health docs, providers are hesitant, and we haven't given good communication guidance. And on the right, patients are hesitant, concerned, pessimistic, don't want to be ostracized. Therapies don't work, and this is aggravated by social and cultural factors.

Implementation of Brain Health Discussions in Practice

So we're suggesting that just like pediatricians do, all of us who take care of people over the long haul have routine discussions about brain health, whether it's primary care, OB/GYN, neurology, general neurology, psychiatry, geriatrics.

And on the right, you know, just again, some pro tips. Just routinely ask questions. "How's your noggin doing? Have you noticed any changes in your memory and thinking? Has your family said anything to you about changes in your memory and thinking? Oh, and by the way, here's the reason I'm asking, it turns out we know how to improve memory and thinking issues if they occur earlier in life." And we know how to reduce future risk. So just the way I'm going to ask you about your heart, lungs, bowels, you know, genital-urinary system, eyes, ears, nose, throat, skin, I'm going to be asking you about your brain health pretty much every time we get together.

Suggested Risk Modification Guidance for Adults

And so, back to Carlos. So on the left, we can talk – and any of your adult patients, right? Talk about all of these things. Carlos’s case, LDL. He's not smoking, thank heaven. His BMI is too high. Let's talk about that. His – we didn't do his – I didn't give you his fasting glucose, but it's likely to be in the low 100s, right? He's got a hemoglobin A1C of 6. Let's talk about that. Let's talk about his systolic of 135. Let's talk about the fatty foods, the Chicken McNuggets that he eats. Let's talk about he doesn't have any aerobic exercise. Let's talk about sleep hygiene. And, you know, five drinks a week. Not something to lose sleep over, no pun intended. But maybe he will benefit from knowing no amount of alcohol is good for him. And then, of course, on the right hearing social isolation, use it or lose it. Depression, head injury, social factors. These are other modifiable risk factors to bear in mind.

Patient Case: Carlos (25 Yr Later, Age 78) Accompanied to Clinic by his Adult Daughter Maria

Boom. Now it's 25 years later, Carlos comes in to see his primary care provider. He's brought in by his daughter, Maria, because she's seen changes. And of course the first thing you're going to do is history, history, history. That's everything. What's happened cognitively, functionally, behaviorally, neurologically? What's up with his sleep hygiene? And of course, all in the context of social and developmental history, his meds, his medications, his habits, his family history. Yes, you're going to do his mental status exam. How's he dressed? How's he comport with you? Is he disheveled, confused, irritable? How about my Nical, what I call my Nical, neurological exam? Is there evidence of focal findings suggestive of a stroke? Right. Is there evidence of Parkinsonism? Are there other findings that I know are abnormal? I might not know precisely what they mean, but they're new, and I want to understand them better, and I might even get a either curbside or actual consult with my neurology colleague.

And then just some tips about early findings and somebody with early neurodegenerative disease, abnormal tone, abnormal stance or gait, arm swing, frontal release signs, and saccadic eye pursuit. Those things are clues.

Then office cognitive testing before any other testing, right? You got that question right. Yes. Digital cognitive assessments are emerging rapidly. Here's a non-profit, I think non-profit anyway, online resource for you that's going to start curating these digital cognitive assessments, give you some guidance if you're interested. Then after history, pragmatic physical and neuro exam and office testing. Then, move on to the other laboratory and imaging testing.

Assessment of Carlos’s Cognition, ADL/IADL, Behavior

So, what do we find from Carlos, to the left? Not remembering names. Trouble with email and texting. Functionally, that could include the texting and email. But also, he's not the handyman he used to be. He's run out of gas. He gets lost. And he's changed behaviorally. It's a mixture of irritable and argumentative but also anxious.

Upper right, of course, make sure he's not sick from something, right? Make sure he's not delirious. Make sure he's not on bad-boy medications. Make sure he's not depressed or having a new-onset or recurrent psychiatric condition.

Then, do the objective testing. I'm giving you a bunch of scores here. I would argue that the Mini-Cog, which is the: repeat these three words. Draw the clock with a hand placed – the hand's placed this way. Repeat the three words. That is not appropriate in my view anyway. In our view, for somebody who already has symptoms, it's okay for a quick test in somebody who doesn't have any symptoms. It has a high negative predictive value, but it's not very good for somebody who has symptoms already.

He went ahead and had the MoCA, the Montreal Cognitive Assessment, and the Mini-Mental State Score, both showing scores in the kind of call it mild cognitive impairment-ish range. You know, between you and me, I'm a little worried about the functional changes, but the cognitive testing indicates those. We would argue that the MoCA or the SLUMS, which I believe may be used in your VA. It is in others anyway, the Saint Louis University Mental Status exam. Those two, the MoCA and the SLUMS, are generally preferred for somebody with early cognitive manifestations. The Mini-Mental that many of us know and have used for years is not so good for early. It has ceiling effects. So, he's in the sort of mildly cognitively impaired range on this objective testing.

Alzheimer’s Association DETeCD-ADRD Clinical Practice Guideline: Tiered Testing for Cognitive Impairment

Dr Tariot: Oh, okay. All right, so our good friends at the Alzheimer's Association published a guide for primary care folks and specialists. Let's see how to apply this to Carlos. You know, he would. He's got cognitive impairment for sure. It's a change. We would go ahead and do the tier 1 tests, you know, metabolic panel, TSH, B12, CBC with diff. You know, homocysteine, likely. ESR and CRP, maybe, depending on your judgment. Structural MRI if available or clinically appropriate; otherwise, CT.

Tier 2 for the "weirdomas", you know, atypical presentation, rapid progression, young age of onset, complex clinical features, a lot of neurological or neuropsychiatric manifestations. What is this? Could it be a cancer metabolic autoimmune disorder, whatever? Tiers 3 and 4, really, primarily for specialists. And then, tier X, you know, might you consider the routine biomarkers for Alzheimer's disease? And we'll get to those in a moment.

Significant Results From Carlos’s Tier 1 and 2 Testing

So, tier 1 and 2. His MRI showed cortical and central atrophy, which is not diagnostic of but fairly typical in emerging Alzheimer's disease. And his clinician said, I think this is mild cognitive impairment, probably based on clinical criteria due to Alzheimer's. Primarily memory loss, that's the amnestic part. You and I might fuss over his degree of cognitive impairment. I'm with you there. But they've got – they want to know, you know, am I eligible for this anti – this therapy that my neighbor’s getting, this infusion therapy? Well, turns out he'd have to wait months for this, either 9-13 months. You know, they may be willing to wait.

And they've heard about these biomarkers. What are the pros and cons of him having these Alzheimer's biomarkers?

FDA-Approved AD Biomarkers (October 2025)

There are three classes of them. Spinal fluid, probably the most sensitive, but people get a little worried about having spinal fluid testing done, although we consider it routine at our place. Has the advantage of probably being the most sensitive. Not that expensive. You get beta and tau measurements. Not available everywhere. Imaging. Basically, that means PET scan, looking at amyloid deposits in the brain. Not available to everybody. And then the lower box of blood. There are two blood tests that have been cleared by the FDA for use.

Pro tip: they’re my most effective at ruling out. So if they're negative in somebody with symptoms, they're probably not very likely to have Alzheimer's pathology. There's a decent risk of uncertain or intermediate results, which means they'd have to go on to PET or spinal fluid testing to confirm. And even for positive tests, there's a decent risk of false positives.

So our rule of thumb is if the test result is indeterminate or positive, we would like to confirm if possible. There are regions of the country where PET or CSF testing isn't practical, and so decision making may be made on the basis of blood tests. We don't consider that optimal, but another area that people probably should have access to the CSF and PET imaging.

What Do You as PCP Do Now?

So, Carlos, at this age, yeah, he may be eligible for beta amyloid antibody therapy. He's in the mild symptomatic range. If he were outside that range, you know, if he had more advanced dementia symptoms, he wouldn't be eligible. You can decide how comfortable you are ordering and interpreting and counseling on blood test results. Those of you in primary care do it all the time with 100 other tests. This isn't that different, I would suggest. Remember that if he's going to get therapy, the earlier the better to not remember. I didn't tell you, but now I'm telling you. It really looks like the earlier, the better.

And to the right, remember that he's eligible for the older FDA-approved oral therapies such as donepezil or one of the other cholinesterase inhibitors. Not memantine yet because it's early, but that's available later. You don't need biomarker testing to initiate these oral agents. And of course, if he starts on therapy, be sure to monitor how he's doing. And of course, give information about clinical trials for people with symptoms. The Alzheimer's Association trial managements for people interested in primary prevention, as Carlos was at age 53. The non-profit, the website, and also our [inaudible] for prevention trials.

Treat The Whole Patient and Family, Not Just the Brain

Lastly, I remember just the brain. We're going to have conversations about safety. We're going to refer to the Alzheimer's Association. We're going to talk about legal and financial planning monitoring for the future. So important, delirium, decline cognitively, or functionally new-onset neuropsychiatric features. We're going to ask how my wife, Laura, the care partner, is doing. And we're going to consider the appropriateness of specialty referral if needed.

Question 2

Dr Tariot: Okay, great. So we've got our 50=year-old who doesn't have concerns but wants to know about future risk. Remember The Lancet Commission report, effective when:

1. With combined with cholinesterase inhibitors for MCI;
2. Only people for with family history or genetic risk;
3. Only effective once symptoms are present;
4. Effective at her age; or
5. Do it because it decreases frequency of cognitive screening.

Pick your vote.

Speaker: Once again, please vote in the poll box or in chat.

Dr Tariot: I'll buy you a sandwich if you get the right answer. I'll come out to Spokane and buy you a sandwich. Off hours so you don't have to report it as a conflict. Okay.

Speaker: We're still waiting for votes.

Dr Tariot: Looks like we'll run about two minutes over. Don't shoot me. Shouldn't joke about that.

Speaker: There we go. There we go. We have several votes for option B, "Bravo."

Dr Tariot: Okay. D would be preferred. Remember The Lancet Commission report. Lifestyle variables can reduce risk when addressed before any symptoms occur. And not just for people with family history.

Question 3

Back to Carlos. What are his non-optimized risk factors for brain health, asthma, partially treated depression, partially treated, cholesterol elevation, overweight. Pick your answer.

Speaker: Once again, please vote. It looks like this time our votes for – our votes are for option C.

Dr Tariot: Perfect. Bingo! You got it right.

Question 4

Okay. And then you finally got somebody with – age 65 with symptoms. Does she have Alzheimer's?

1. Reassure her;
2. Perform cognitive assessment before other labs and imaging;
3. Standard labs and imaging now
4. Standard labs and genetic testing.

What would you pick? Then we'll go to this CME information for those who are interested.

Speaker: Please vote. All right. Thank you. It looks like we have 100% for option B.

Dr Tariot: Oh, yay. You're good students.

Q&A

Speaker: Thank you so much, Dr Tariot. Again, we're taking any questions you may have. I did see one that came through, Dr Tariot. Oh, there was one that said. Are any of these treatments used in TBIs?

Dr Tariot: That's an excellent question. The FDA-approved treatments for Alzheimer's disease are not FDA-approved for treatment of, let's call it, neuropsychiatric manifestations of TBI. You know, some clinicians will try, for instance, the older FDA-approved oral agents, that's very off-label. So, no, and unfortunately, you all on the federal system are probably, you know, the national experts in managing TBI, much more so than people in memory clinics like mine. And no, you didn't ask it, but no, the GLP-1s don't work for symptomatic Alzheimer's disease. Definitive testing has been done, and the answer is a slam dunk, no. A bit of a disappointment. Okay, folks.