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

Dr. Irina Anna Skylar-Scott (Stanford University School of California): Thank you so much. It is an absolute joy to be with you all today. And today, we're going to be talking about whether cognitive checks can be used as a new vital sign.

Content Director and Disclosures

So these are my disclosures.

Your long-time patient is now 50 years old, and you're discussing the importance of brain health with her for the first time. Which of the following would you tell your patient when discussing ways to optimize your brain health before she has any symptoms of cognitive decline? Is it:

A. It's effective when combined with cholinesterase inhibitors for mild cognitive impairment;

B. It is most effective for those with family history and/or genetic risk for Alzheimer's disease;

C. It's most effective once mild cognitive impairment has developed;

D. It can be effective when addressed at any age; or

E. It reduces the recommended frequency of cognitive screening;

So, you know, in the case of this patient, you know, we would not start cholinesterase inhibitors in a person who is cognitively unimpaired. You know, we certainly want to take into account family history and genetic risk, and certainly those patients may have a higher degree of concern. I wouldn't wait to start talking about brain health and, you know, preventative lifestyle factors until they are already at the level of MCI. Those can be discussed in advance.

So I would agree, you know, I think B to a certain extent as well as D, it can be effective when addressed at any age, but it doesn't necessarily preclude you from cognitive screening. So that is something that you would continue to do to make sure that you're not missing anything but great - great participation across the board. Okay. So effective when addressed at any age.

Pretest 3

All right. Here's another question for you all. So a 53-year- old man is referred by his primary healthcare provider to a neurology clinic for evaluation of hand tremor. This patient's history and review of systems include some ongoing health issues that are well managed. And in the neurologist discussion with the patient and the note back to the primary, which would you mention for close monitoring and re-evaluation as most likely to mitigate the risk of developing cognitive impairment or dementia? Is it:

A. Drinking four cups of coffee per day;

B. History of depression, currently treated with an SSRI with a PHQ-9 score of four, range of zero to 27;

C. Blood pressure in the of 152 over 85 currently on an ACE inhibitor; or

D. Elevated BMI of 28, regular exercise, 30-minute walk four to five times weekly;

You know, maybe asthma is less of a concern in this context, but certainly the history of depression is important because we know that depressed mood can affect cognition. So that's something to continue to keep an eye on and check in on with the patient.

LDL is important because it's a vascular risk factor and it's a risk factor for vascular cognitive impairment, including vascular dementia. So I think if the LDL is still 120, that's something that you want to keep an eye on and counsel the patient on.

And then finally, the BMI is an important risk factor, but I'm pleased to see that this patient is exercising regularly. We recommend a minimum of 30 minutes a day, five times a week of moderate intensity aerobic exercise. And so one thing to maybe check in with this patient on is whether they're - what the intensity of their exercise is and whether it's appropriate here.

But - but all great thoughts here, all largely important. Just to answer these, you know, blood pressure is an important risk factor as well for vascular cognitive impairment and coffee less important in this context.

          Pretest 4

Okay, so we've got another pretest question. Oops, sorry. So this is a 65-year-old. She's had some anxious symptoms following a car accident, is diagnosed with PTSD at a community clinic. Six months later her anxiety is much improved with ongoing SSRI therapy and psychotherapy, but she's mentioned she's had a few occasions where she got - she's gotten lost while driving and has forgotten people's names. She's concerned that these could be early symptoms of Alzheimer's disease. This is going to be a common scenario in your clinical practice. What steps could you take to address her concern? Is it:

A. Reassure her that occasional memory lapses are normal with aging, but order blood biomarker testing to address the concern;

B. Perform a comprehensive cognitive-behavioral assessment;

C. Order a cognitive laboratory panel to rule out medical issues that can affect cognition, neuroimaging to rule out issues such as tumors and infarcts or - and APOE genetic testing; or

D. Contact a family informant to discuss her driving.

Okay, great. So you know, with the last two pretest questions, what we learned is that it's never too early to start looking at preventative risk factors and talk about cognitive health with patients, even if they're cognitively unimpaired, whether it's vascular risk factors or psychiatric risk factors. But here we now have a patient who's coming in with cognitive concerns.

This is not a patient where I would reassure her and stop there. This is a patient where I would certainly perform a cognitive assessment. I would also try and get information from a collateral historian, somebody who knows them well. That could be a family member, but, you know, if patient - if a patient is living on their own and others don't know him or her, or in this case, the 65-year-old woman, well, I get creative.

I'll ask a neighbor. I'll ask their pastor. I will ask you know - if nobody else, I'll ask their primary care physician. But I'm always looking for somebody that I can ask and find out collateral information about. So I would certainly start with a cognitive behavioral assessment and see whether we're seeing any evidence of objective impairment in this patient.

On the subject of APOE testing, I'll just mention we don't routinely test it in everybody. We will test it in people who have a confirmed diagnosis of Alzheimer's disease, where we're wondering about their risk for anti-amyloid therapy side effects, but - because APOE can tell us whether their risk is increased or decreased. But I don't get APOE testing routinely in everyone, especially if they're not considering anti-amyloid therapies.

Learning Objectives

Okay. All right. So here are some of our learning objectives today. We want to implement some expert recommended neurocognitive assessments and emerging diagnostic tools. We want to look at preservation strategies. We want to develop personalized multidisciplinary care plans together.

What Is That We Are Trying to Prevent?

So let's start with what is it that we are trying to prevent?

Typical Course of Dementia

So a key point here is that the changes that we see as with - as a result of aging and cognition is not the same as mild cognitive impairment or dementia. It's a different trajectory. And it's a question I get in my clinic all the time. I'm getting older. Isn't this all just a part of normal aging? And the answer is, well, it depends. If you're - you know, if you have demonstrate that you have mild cognitive impairment or dementia, that's different from age-associated memory impairment.

With age-associated memory impairment, you might get a history of, you know, I walk into a room, and I forget why I walked into the room, or I sometimes have trouble finding the right word, but often it comes back to me.

You know, I might occasionally forget where I left my keys. Things along those lines can all be part and parcel of age-associated memory impairment. But with mild cognitive impairment, where we're looking for is a decline from baseline, both subjectively and objectively. And meaning that they - either they or someone around them reports it and objectively meaning on your cognitive assessment in your clinic.

And then in general with mild cognitive impairment or MCI, they're independent of their ADL. So they are able to function independently, they're managing their medications, finances, appointments, etc., without any errors, without any difficulty.

And then by the time they get to the level of dementia, when they proceed from MCI to dementia, not only do they have subjective and impairment - impairment and a demonstration of progressive decline over time, a change from their cognitive baseline. They also start developing, requiring assistance with ADLs. And it starts with instrumental activities of daily living, I-ADLs, like meds and finances, and then eventually progresses to more basic I-ADLs like hygiene tasks.

Not All Dementia Is AD

So the key other point is not all dementia is Alzheimer's disease. In fact, there are many different causes of dementia. And it's certainly the case that Alzheimer's disease is the most common cause of Alzheimer's disease and the one - of dementia and the one we see most frequently. But we can see vascular dementia, Lewy body dementia, frontotemporal lobar degeneration, and many other causes of dementia, multiple systems atrophy, primary progressive aphasia, the list goes on and on.

But another key point is that, you know, on these quiz questions, sometimes there will be one cause of dementia. But in the real world and in the patient setting, very often there's co-pathology. So patients might have Alzheimer's disease and vascular dementia affecting them at the same time and that's worth keeping in mind.

Major Changes in the Brain due to AD

So what's happening in our brain when we develop these changes due to Alzheimer's disease? Well, first of all, on the left, I'm showing you what the atrophy that can occur and you get what's called a temporal parietal pattern of atrophy and Alzheimer's disease. So the parietal lobes in the back of the brain get atrophic or shrunk or shrunken. And then the temporal lobes on the side get shrunk, especially the mesial temporal lobes on the kind of the inside where the hippocampi are, the memory centers of our brain. And so many of you will be familiar with plaques and tangles.

So what happens is first you have amyloid protein that accumulates in the brain and eventually forms these plaques. And you can think of amyloid protein, like the red carpet that gets laid out at an event. And then sometimes decades later, you get this tau protein, which forms these neurofibrillary tangles. And it's like the celebrity that saunters on much later onto this red carpet.

And then you get all these downstream effects, whether it's inflammation, membrane dysfunction - dysfunction, and neuronal loss, among others that occur following the tau accumulation.

AD Pathophysiology Begins Decades Before Symptoms Appear

And so, as I was alluding to earlier, the - these pathophysiological changes can occur decades before we see any symptoms. And this fact actually blew me away when I first learned it. But by the time you get to the level of MCI, mild cognitive impairment, you've lost at least half of your hippocampal neurons, the neurons in the memory centers of your brain. And so that's why a lot of clinical trials are now moving earlier and earlier in terms of attempted interventions. And there are several ongoing trials now where people are looking at what's called preclinical AD before any symptoms develop, to see if we can intervene earlier before you get these devastating neuronal losses and this devastating atrophy.

But, you know, these earlier stages do present an opportunity for earlier diagnosis, especially with biomarkers coming online.

Time course of AD

And so we talked a little bit about this, but these - so these are called the JAK curves. And I have a lot of affection for them. They show, you know, the initial accumulation of tau followed by medial temporal lobe tau, and then neo - and then the spread of tau from the temporal lobes on the side of your brain to the neocortex, the rest of your brain, followed by these neurodegenerative atrophic changes and the clinical symptoms. And you'll see this - the reason I have affection for these curves is you'll see them in every single talk that you will ever see about Alzheimer's disease for the rest of your life. You'll always see these JAK curves. So I've seen them in many in talk, but anyway, sort of nostalgic.

So coexisting pathologies can move these curves along and speed up the process and speed up the - the - the symptom onset. They can also lower cognitive reserve when you have multiple pathologies occurring all at the same time. And this slide also points out that there are different levels of severity of dementia: mild, moderate, and severe. And so as I was saying, you know, we start out with mild dementia where you get those - the instrumental I-ADLs affected where people start making errors with things they were able to do before, like managing medical appointments and then all the way to severe dementia where they are don't recall the steps of bathing, for example, or the steps of getting dressed.

Clinical AD Staging

And so - so we start out with asymptomatic Alzheimer's disease. It's also known as preclinical Alzheimer's disease, where you have biomarker positivity in the form of blood based biomarkers or spinal fluid testing or amyloid and tau PET, but they haven't developed any symptoms. And then there's also a stage zero genetically determined AD. This is all in the 2024 Jack et al. Alzheimer's disease clinical and biological staging criteria. So the reference is at the bottom there, but that's a really useful reference if you're trying to remind yourself of these stages.

But if you have genetically determined AD, then you're at stage zero. And then you eventually you progress to stage II, where you're starting to develop some mild symptoms, but your objective scores are normal, and so you don't meet criteria for MCI.

And then by the time you get to stage III, that's the equivalent of MCI. And then stages IV to VI are the equivalent of mild, moderate, or severe dementia, respectively.

Biological AD Staging (ATN Framework)

And so in this ATN biological staging frame - framework, which was updated in 2024, you have this. So ATN, A stands for amyloid, T stands for tau, and N stands for neurodegeneration. And so you have core biomarkers for amyloid including either an amyloid PET scan or CSF amyloid levels or a plasma A-beta42. We also - I don't tend to get the plasma A-beta42 in the clinical setting, I will get the plasma p-tau217. And despite the name which has tau in it, it - p-tau217 in plasma actually correlates best with amyloid presence in the brain with amyloid PET.

And so that's something to keep in mind. It's really giving you some information about amyloid in the brain. And then there are CSF A-beta42 measures as well.

And then you can measure tau using biomarkers again to increase your diagnostic confidence of diagnosing Alzheimer's disease. You do want to, you know - again, to diagnose MCI, they need to have the subjective impairment and the objective impairment in addition to biomarker positivity. But if you're measuring tau, there are a few options. Tau PET is clinically available. There is one tracer that's been FDA-approved, or you can get spinal fluid tau measures both total tau and phosphorylated tau markers.

MTBR is not yet clinically available, but the hope is that it'll be available soon because it's thought to be a measure of later stage tau. So in contrast to p-tau217, which is more correlated with amyloid levels, the MTBR is going to be correlated with actual tau levels in the brain. So stay tuned for that.

If you - if you invite me back in a - in a couple years, maybe I'll have some good news on that front, but we'll see.

Integrated Biologic and Clinical AD Staging

So here's - here's a little bit of a summary. So this is looking at the biological and clinical stages together. And this is used a little bit more in the research setting than in the clinical setting. But for example, you could be in an initial biological stage, like A, and then the stage 1 clinical stage. So you're in stage 1A and then it progresses all the way to stage 4 to 6D or 6D is really the last stage. But we use this a little bit less commonly.

But the idea is that we now think of Alzheimer's disease as this clinical biological entity. So we don't need to make a diagnosis solely on the basis of the clinical picture, although you certainly still can. But we can make it on the basis of all the information that's now available to us.

Early-vs Late-Onset AD

Okay, so a little bit about early-onset Alzheimer's disease versus late-onset Alzheimer's disease. So in the case of early-onset AD, the symptoms are really starting before the age of 65, and it only represents about 5% to 10% of all AD causes. But you shouldn't associate - you shouldn't automatically assume that if somebody has early onset Alzheimer's disease with symptoms before 65, that they have a genetic mutation. That said, if somebody has a characteristic family history, they - you know, their mother had Alzheimer's disease, their mother's mother had it, that kind of thing, where it's in every generation, I will do genetic testing in those early onset patients, especially if they're interested in it. And they would like - they would like that information to guide their discussions with children and grandchildren about their respective risks.

You may have heard that people with down syndrome or trisomy 21 are at increased risk for Alzheimer's disease. That's because one of those rare genetic autosomal dominant genetic conditions, which is caused by the gene APP. APP is on chromosome 21, and these patients have three copies of chromosome 21. And so that's why they have increased risk of Alzheimer's disease. So you'll see it more commonly in people with down syndrome.

And these - all of these genes cause abnormal amyloid processing to increase the risk of AD. But the vast majority of patients that you're going to see have late-onset Alzheimer's disease with symptoms that start after 65. And so some - many of you will be familiar with APOE, which I briefly mentioned earlier. It is a gene that confers increased or decreased risk or neutral risk for Alzheimer's disease, but it is not a deterministic gene.

So if you have one or two copies of E4, you're at increased risk for Alzheimer's disease. But it doesn't mean that you will definitely get Alzheimer's disease. And if you have one or two copies of E2, that can decrease your risk for Alzheimer's disease, especially. It turns out if you're E2/E4, then the E4 cancels out the beneficial risk of E2.

So - but if you're E2/E3 or E2/E2, that means you may have decreased risk of Alzheimer's disease. And then if you’re E3 - E3/E3, which is what is the most common genetic profile, then you have neutral risk for Alzheimer's disease. But again, it just conveys risk. It's not deterministic.

And - and so-late onset Alzheimer's disease are, you know, caused - are caused by APOE and other genes along those lines that confer a little bit of increased risk. And then lifestyle factors, environmental risk factors. And the single biggest risk factor is age.

The Coming Dementia Pandemic

Okay. There - and speaking of which, there's this coming dementia pandemic. I'm so sorry to be the bearer of bad news, but, you know, you have seven million Americans living with Alzheimer's disease now, but that's supposed to double in the future. And we have a shortage of dementia care specialists. So hopefully that's why you're here hoping to learn about dementia care because there's this really growing - there's this growing need. Oftentimes we're diagnosing patients too late before we really have the opportunity to reintervene with therapies like anti-amyloid therapies. And so this is a time where we really - we need to have caregivers who are - who have knowledge of dementia.

What Does the AD Population Look Like?

And so what does this population look like? You know, the vast majority are going to be over the age of 65 because as I said, the single biggest risk factor is age, but we are going to see people in their 60s and 70s as well. And as many of you will know, AD tends to - affects women more than it affects men, although certainly both are affected. And so we estimate that we're going to see more - more women affected by this dementia - ongoing dementia pandemic.

AD Risk Varies by Gender, Race, and Ethnicity

So the other thing is, you know, dementia risk can vary depending on your gender, your race, your ethnicity. So the estimated lifetime risk for women is much higher than it is for men. By the time your age 45, if you're female, the estimated lifetime risk is 19.5%. If you make it to 65 - age 65, then your risk at that point in time is 21.1% versus 12% in men.

And the risk if you're of developing dementia due to Alzheimer's disease is higher if you are Black or Hispanic/Latino as well. And I think there's a lot of ongoing work to try and figure out what the basis of the risk is. And some of that is going to be environmental, genetic. So it's - I think it's an area of very active inquiry.

What Is Brain Health?

So what is brain health? So the American Academy of Neurology came out with this statement. Brain health is a continuous state of attaining and maintaining optimal neurological function that supports one's physical, mental and social well-being through every stage of life.

A Little Break...

So we're going to take a little break before we continue with some corny jokes. You will learn very quickly that I am a lover of corny jokes. So how does a brain say hello? A brain wave. What is a sleeping brain's favorite musical group? REM. What has heads and tails but no brain? A coin. And finally, when does the brain get afraid? When it loses its nerve.

Okay, just a little - little break. Just something to give your brain a little break before we continue.

How Can We Help Prevent Dementia Without Medication?

Okay, so we're going to talk about how we can help prevent dementia without medication.

Patient Case: Alice

And so we'll start with this patient case. This is Alice. She's 51 years old. She's an accountant, divorced. She has a teenage son. She visits your clinic once or twice per year for follow-up of chronic conditions, including migraines, bipolar disorder, and mobility concerns. She mentions her widowed mother had Alzheimer's disease. And she's a caregiver for her widowed mother.

And her mother has been having difficulty bathing and dressing herself and she's considering home – in-home or residential care. So Alice is now considering her own future. She's concerned that she will be a burden to her son. She's asking if - she's asking you is there anything I can do to reduce my risk of dementia or plan ahead? And she wants to learn about any FDA-approved treatments or any research.

Time for Reflection: How Would You Respond to Alice?

So let's reflect and tell me - think about how you would respond. Is there anything she can do now at this point when she's still cognitively unimpaired?

How Can We Help Alice Optimize Her Cognitive Health, Reduce Her Risk of Dementia?

So - so here's a little bit more about Alice. She - we talked about her family history. She also has an elevated BMI. Her blood pressure is 135 over 85. She has an A1C of six. So she started to meet criteria preclinical - for prediabetes, sorry. She has an elevated total cholesterol. Her LDL - she's on atorvastatin. Her LDL is not so bad. She says she's too busy to go to a gym, but she walks. She eats a low fat diet but orders takeout. She drinks five alcoholic drinks. She gets six to seven - seven hours of sleep. So we can reflect on which of these you would discuss with your patient, Alice.

Time for Reflection: How Can We Help Alice Optimize Her Cognitive Health, Reduce Her Risk of Dementia?

I mean, I will just - I'll talk a little bit more about these lifestyle factors in just a moment, but I'll just reflect on these. You know, certainly you could address her BMI via diet and exercise and that would hopefully help with the A1C as well. The diet that's been shown to be best for brain health is the Mediterranean diet. So that's something worth discussing.

It's great that she's taking a walk around the neighborhood, but again, we want to make sure that it's moderately intense aerobic exercise, which means basically that she can have a - maintain a conversation while she's exercising, but it should be a little bit difficult. It should be a little bit of a strain to have a conversation.

So if it's sort of a leisurely stroll, we can encourage Alice to - to try and pick up the pace when she takes these walks. You know, other people will, you know, get equipment into their home, whether it's a stationary bicycle or treadmill. And then, you know, we can talk to her about her diet, as I've mentioned. And then sleep is really key here because we know that people - if people aren't getting adequate sleep, they - that's one way to accumulate amyloid because we - most of our amyloid that gets cleared during sleep. And so we want to talk to her about getting at least seven to eight hours nightly.

Cumulative Impact of Modifiable Risk Factors for Dementia

Okay. So in 2024, the updated Lancet Commission report was - was published and they identified a number of different modifiable risk factors that all together can account for 45% of the risk of dementia, which is substantial. And it's - and it's across the lifespan. So everything from education level in early life to hearing loss and LDL levels in midlife, diabetes and smoking, air pollution, and visual loss.

So take a moment to look at this list because I do think it bears emphasis. And these are all areas where we can potentially intervene with our patients, both one-on-one. But these are also areas to think about at a societal level, what can we be doing to - to decrease dementia risk as a community?

WHO 2022 Recommendations Risk Reduction of Cognitive Decline and Dementia

Okay, so - so I talked a little bit about this. These are the World Health Organization recommendations for risk reduction for cognitive decline and dementia. And again, it's never too early to start talking about these factors with our patients. Whether it's weight management or blood pressure management, nutrition, obviously, tobacco cessation, alcohol use, cognitive interventions.

The - you know, there's not a lot of evidence to support taking vitamins unless somebody has demonstrated a vitamin deficiency from a cognitive standpoint. So certainly if their B12 levels are low, then we would recommend supplementation. But if their B12 levels are in the normal range, they don't need to just take a prophylactic multivitamin from a cognitive standpoint.

And some of these conversations are really challenging. You know, it can be - behavioral change is hard. It can take several visits. It can be challenging to get somebody to decrease their alcohol use, for example. But the key thing is really to establish a rapport for them. I try to bring these up - these types of topics up over multiple visits. Get them thinking about it. You know, you can do a little bit of motivational interviewing. How motivated are you to cut down on your drinking or stop drinking? Why? And then, you know, they'll say five out of 10 and you'll say, "Why is it five and not zero?" And try and get them motivated to change some of these lifestyle factors.

Depression and Dementia: A 2-Way Road

Sometimes giving them this information that this can - this - there's true literature, there's real evidence to suggest that this can decrease dementia risk is important.

Another area that's really important is addressing dementia as a risk factor. And we now think that there's this sort of bidirectional relationship between depression and dementia. So depression can increase risk for dementia, and then the biological pathways that are affected when you start developing dementia can in turn lead to depressed mood.

It certainly - and certainly when people are - have more insight in early stages of their dementia process, you know, even being aware that they're changing cognitively can lead to depressed mood. And so you have a lot of factors at play here, but that is certainly an area where we can intervene. Where we can provide medication, where we can recommend psychotherapy.

Association of Sleep Disorders With Dementia

I was talking with about sleep a little bit earlier, but you can get increased sleep latency or decreased sleep duration. And both of those are associated with dementia risk. Again, because you're accumulating these proteins in your brain and you're not clearing them adequately. And you can get sleep disturbances that co-occur with other risk factors for dementia to create a perfect storm, unfortunately. And so we really want to recommend that our patients get seven to eight hours of sleep, that we counsel them about sleep hygiene. That's really key.

So you have to find the time for this, of course, but take time out of your visit to say, "You need to be going to bed at the same time every day. And you know - so that you can wake up at the same time every day. You need to associate your bed with sleep. You need to avoid screen time the hour before sleep. You want to make sure that you're increasing light when you wake up in the morning. You know, getting rid of light when you're - when you're getting ready to go to bed so that your brain has as many cues as possible to say, this is sleep time. This is wake time."

Happy to answer any questions about sleep hygiene or any of the things we're talking about at the end.

FINGER Study: Multidomain Lifestyle Modification

So the FINGER study was a study in 2015 that looked at multimodal lifestyle interventions. So the idea here is what if we throw the kitchen sink at it? What if we do everything all at once? Nutrition, exercise, cognitive training, management of vascular risk factors all at the same time.

So the people who were enrolled in this two-year study were all cognitively unimpaired, but were demonstrated - demonstrated an increased risk for dementia on the basis of their risk factors. And so they were randomized either to a structured intervention where they were doing all of these tasks or an - you know, a placebo intervention education intervention where they were given some information, general information about these lifestyle factors.

And in this study, people seem to benefit over time in terms of both their executive functions or their ability to organize, plan, problem solve, multitask. And then in terms of their processing speed as well. Interestingly, these interventions did not help episodic memory, specifically. They did help global cognition, I think in part because the changes, the findings you see here in executive function and processing speed drove that change in global cognition.

But this - this was a positive study, a positive phase III study that showed that multimodal intervention could modestly improve or maintain cognition - cognitive function in - in older people who are at risk and cognitively unimpaired.

And so subsequent to the FINGER study we've had - we've now had the US POINTER study in the United States. And this is again a multimodal intervention. Two years, phase III. These were all cognitively unimpaired people. They were, again, randomized to either a structured intervention where they are meeting with an exercise class, they're getting diet coaching, they're meeting with a group to get social intervention. They're doing cognitive training exercises, computerized cognitive training exercises versus the self-guided intervention where they're told these are things you should be doing.

And again, there was a significant difference between the two groups, although interestingly both groups seem to benefit.

So even if you just relay this information to your patients about what is helpful for their brain health, that can lead to a benefit for them over time. And so there was - but there was a significant benefit of the structured intervention over the self-guided intervention. And so it's important to emphasize all of these different risk factors to these patients, because the literature increasingly shows that if you can do these multimodal interventions where you're trying to target all of these risk factors at once, that that tends to have a greater benefit.

Determinants of Brain Health Across the Life Course WHO Position Paper 2022

So you know, we've talked about some of these, but we can really do a deep dive on some of the brain health interventions across the lifespan. This was the position paper from the WHO. So things we haven't discussed yet, but you know, maternal health, infections, health behaviors, traumatic injuries.

We now know that, you know, recurrent TBIs are a risk factor for dementia. Chemical use, protection from radiation, air and water quality, lifelong learning, social networks, care support. So all of this can have an impact. So take a moment to take a look at this slide because there are a lot of places where we can counsel our patients or intervene or create dedicated, personalized care plans for our patients based on their specific areas of risk.

Key Points: What Will Help Patients Maintain Their Brain Health?

Okay. So if you only have a few minutes though, and you can't focus on all of those topics I presented in that last slide, then these are the areas where you really want to lay your emphasis. And that's everything from aerobic exercise to sleep hygiene, social interaction, spending time with friends and family, mental activity. The idea of use it or lose it is very true when it comes to the brain. So to the extent that people - that your patients can be doing cognitively challenging activities, that's really important.

So all food for thought, all areas that we can all improve on ourselves, and we can counsel our patients on.

Neurology

So here's a little brain break for you all. Another corny joke.

How Is AD/ADRD Detected and Assessed in the Clinic?

Okay. All right, so now we have some time to talk about Alzheimer's disease and Alzheimer's disease-related dementias and how they're detected and assessed in clinic.

Patient Case: Alice (25 Yr Later, Age 76)

So - so now Alice is a little - this is 25 years old later. So she's older. She's now 76. She's accompanied to the clinic by her adult son, James. So before you do any cognitive testing, you want to get a history. It's very important. The acuity can really guide your differential diagnosis. If you're getting many years of cognitive impairment, then you - you're thinking along the lines of progressive dementias versus, you know, this has been going on for a few weeks or a few months. Then you might be thinking along the lines of a rapidly progressive dementia like CJD.

And so you want to characterize the nature of the symptoms. What was the earliest and most prominent symptom? If the earliest and most prominent symptom was language impairment, then you're thinking primary progressive aphasia.

So - so that will guide your differential diagnosis. And then I do a deep dive on function because I - I want to know, are they managing their medications? Did they - if so - if not, do they ever manage them before? Are they not managing them now because there's, you know, a culture within the family where kids take over for parents and take care of their patients? Or is it because there were errors and mistakes made and the patient used to be able to manage their meds, but now they can't?

So I go through lots of different activities of daily living and do a real deep dive there, because I want to know what the level of severity is.

And then, you know, you can probe for unsafe behaviors and do wandering counselling. I'm happy to talk about that in the Q&A.

And then, you know, I have to ask everybody about driving because that's - that's really key. Again, a difficult conversation to have with patients and families. That's - for a lot of this, the collateral historian is really key, as I was mentioning. So the adult son, James, is going to be really important to get a sense of a lot of this, especially if - if the patient is at the level of dementia and they're losing insight into their own impairments.

Assessment of Alice's Cognition, ADL/I-ADL, Behavior

So - so it turns out in this case, Alice is not remembering significant friends from the past or James's children's name. So that's a change for her. She's having difficulty sending emails and texts, which in the past she did with ease.

Again, you want to know what the baseline is. If she was never somebody who sent emails or texts and she still doesn't, that's of course less of a concern. But in this case, there's a clear change. She's having difficulty with her I-ADLs. She's having - she's more argumentative and irritable, which is often a history you get with our patients who are developing neurodegenerative conditions.

She's anxious when she's forgetful. And so first of all, you want to rule out the areas where you can intervene. Is this a delirium? And the time frame can really help you with that? Are there any inappropriate or risky meds? I do a deep dive on the med list. You know, are there - is - is this patient on an antihistamine like Benadryl? Are they on any bladder meds that can affect cognition? Or, you know, are they taking - are they on opioids or benzos,? All of which can affect cognition.

So this patient had a mini-Cog. They scored three out of five. So sort of on the border. But the MoCA is clearly impaired, 19 out of 30. 26 is sort of the threshold for MoCA, 26. And then - and the MMSE is also low, 23 out of 30. So, you know, I would not - this table in the lower right corner is not - I would this is not gospel. I mean, it's a little bit of a guideline, but you really want to rely quite a bit on the history to determine what level of severity this is.

But, you know, in basic terms, this patient had a MoCA of 19. So I don't know if we got - we didn't get a - we got a history of I-ADL impairment, but not ADL impairment. So, you know, I'm not going to say that this - this patient is at the level of a - do we - let me just make sure that. I will tell you my impression in a little bit, but I would not call this moderate yet based on the history.

So - so I'll just share with you before we continue that I think Alice is - I'm concerned that Alice is at least at the level of mild dementia because she is developing cognitive impairment. She has objective impairment on her MoCA and her MMSE, and she is developing new difficulties with her I-ADLs.

What Should Clinical Evaluation Include?

Okay. So your clinical evaluation should include a focused history neuro exam. Standard labs, including a vitamin B12 level and a TSH, structured brain MRI imaging that - American Academy of Neurology recommends that these patients where you're concerned about MCI or dementia should get an MRI scan, in part to rule out structural causes of cognitive impairment, big bleed, big stroke, big mass. But it can also be helpful because you can look for characteristic patterns of atrophy. If this - if you're worried about frontotemporal dementia, for example, you'll have characteristic atrophy in the frontal lobes and the temporal lobes on the side.

And then - and then biomarkers can guide your - can help. Once you've established a diagnosis of MCI or dementia, biomarkers can - and you have a pre-test probability, let's say, of you think this is Alzheimer's disease and you can get these tests to supplement your diagnostic thinking. So there are a number of different tools you can use for your cognitive screens, everything from the mini-Cog if you have no time at all, to a MoCA or a SLUMS exam.

The MoCA takes longer than the MMSE. But MMSE doesn't capture people who are in the earliest stages of cognitive impairment, so often it won't capture MCI. Sometimes it won't capture mild dementia. And it's not a great test for testing executive function if you're worried about FTD. But if you don't have a lot of time - if you don't have enough time to do a MoCA, then the MMSE is - can be your go to. And certainly I use the MMSE in patients where I think that they have a moderate or severe dementia by the - based on the history.

And then for those of you who have neuropsychological testing available to you, you can use that as a supplement. It's helpful in patients where they have a lot of cognitive reserve. They're doing reasonably well on the MoCA or the MMSE, but you want to make sure that they're not - they don't have objective impairments.

It's also helpful where the diagnosis is in question. Maybe you're trying to determine you're between two different types of dementia, and you want to understand the - the profile that could point you in a particular - to a particular dementia etiology. I - you know, sometimes patients want that extra level of certainty or they want to establish a baseline that can be a point of comparison down the road. And you can use neuropsychological testing to say - to tell patients in detail how they're progressing, what are their cognitive strengths or weaknesses? But it's not - it's certainly not something I get in all of my patients. It really - it's very circumstance dependent.

Alzheimer's Association DETeCD-ADRD Clinical Practice Guideline 2024: Tiered Testing for Cognitive Impairment

And so - so the Alzheimer's Association recommends tiered testing. I think we've gone through a lot of this but you will have access to all of these slides. So all of this will be available to you.

FDA-Approved AD Biomarkers (October 2025)

And so we talked a little bit about FDA-approved Alzheimer's disease biomarkers, but again we now have both amyloid and tau PET that are clinically available in some centers. We have spinal fluid testing. There's good concordance between spinal fluid and PET testing. I tend to get spinal fluid testing in patients where I want to know both amyloid and tau levels. And I - especially in early onset patients where I want to be as definitive as possible with the diagnosis. Because in those early onset patients, you're really impacting their lives. Some of them may still be working, some of them may still be caregivers for children.

And so I think an extra level of certainty can be really helpful here. But we're really lucky that we're now in this biomarker era that we have blood-based biomarkers that are clinically available. The first FDA-approved blood test was approved in May of last year. And, you know, I anticipate that more and more tests will become available.

P-tau217 is really the test that's the most accurate amongst the blood-based biomarkers that are used in clinical use in addition to the p-tau beta42 ratio - P-tau217 A-beta42 ratio. That ratio is currently on pause because some of the recent batches haven't been accurate. And so you cannot get that clinically temporarily. But I imagine - I anticipate it'll be back online soon.

But in order to be a good blood-based biomarker, you want to make sure that the biomarker has at least 90% sensitivity and at least 90% specificity for - to be a great - a good blood-based biomarker for what you're looking for.

Negative and Positive F-Florbetapir PET Scans

You can also get FDG - Oh, sorry, this is amyloid PET scan. So this is the difference between a negative and an amyloid PET scan. And so what happens is that you have loss of the grey white junction on these scans. So you get amyloid deposition in the grey matter. And so whereas you can kind of see this sort of X like projection on the left with this negative amyloid PET scan, you lose that white delineation of the white matter when you have a positive amyloid PET scan in these patients.

And you know, you are required to establish that the patient has amyloid in their brain before you recommend anti-amyloid therapies in patients with Alzheimer's disease. And so it's important to either use a spinal, you know, lumbar puncture or PET scan. Most people are not using blood-based biomarkers yet as the only biomarker for determining anti-amyloid therapies, although I anticipate that that will happen in the future.

Biomarker Assessments to Gauge the Likelihood of AD Pathology

This is looking at - many of you will have seen this in the past. This is what you might get back if you get spinal fluid testing in a patient. If they're in that lower right corner, that suggests that their profile is consistent with Alzheimer's disease. If they're in that upper left corner, that means that it's not consistent. And then sometimes you get these equivocal results.

The CSF amyloid level is counterintuitive. The level is high - I'm sorry. The level is low rather than high. And then the phosphorylated tau and total tau levels are high. So you have to remember that the amyloid level has to be low in the spinal fluid.

Biomarker Assessments to Gauge the Likelihood of AD Pathology

Okay. So the patient A versus patient B consistent not consistent with Alzheimer's. And so it's really important to use polypropylene tubes if you're doing a lumbar puncture in these patients. So you can't use the standard tubes that come in the LP kit. You have to get these polypropylene tubes because A-beta42, the amyloid protein can bind to the regular tubes, and then you're going to get a false result if you're not using the right tubes for these lumbar punctures. So polypropylene tubes, right?

Commercially Available Biomarkers for AD

Okay. So these are all the different biomarkers that are commercially available for Alzheimer's disease. We've gone through quite a few of them. You know, again, I don't routinely get blood-based P-tau181 or A-beta42 or A-beta42/40 in the blood because those tests have not been shown to be as accurate as the P-tau217 or the P-tau217 phosphorylated to non-phosphorylated ratio, although that one's used a little bit more in the research setting. Or the P-tau217, A-beta42 ratio. So anything that has P-tau 217 in it is - is probably a good call.

Treatment: Where Are We Now?

Okay. So the assay really does matter. Okay. A little bit on treatment. We're going to wrap up now. Where are we now? So we're really fortunate to be in this area - era of disease-modifying therapy. So many of you will be familiar with the symptomatic therapies.

Tacrine is no longer in clinical use because of LFT abnormalities, but we do - so - but we do use anti - sorry, we do use cholinesterase inhibitors like donepezil, rivastigmine, galantamine and an MDA receptor antagonists like memantine. And then we have these anti-amyloid therapies. These are antibodies that clear amyloid from the brain. Aducanumab is no longer on the market, but lecanemab and donanemab are both available for our patients - in patients with MCI or mild dementia due to Alzheimer's disease.

2 FDA-Approved Antiamyloid mAbs for AD

And so - so lecanemab is an intravenous infusion once every two weeks. The - they are asking for FDA approval for subcutaneous injections rather than intravenous infusions. So stay tuned on that. We may hear more about that later this year.

Donanemab is an intravenous infusion every month. In - donanemab has stopping criteria. So once you get below a certain amyloid PET threshold, a certain amyloid centiloid value, you can actually stop the donanemab.

In contrast, lecanemab is supposed to be an indefinite therapy, so after 18 months you can switch over to either monthly intravenous infusions rather than every two weeks, or you can switch to weekly subcutaneous injection - injections done at home.

And so again, you want to establish that patients have amyloid in their brains before you refer these - them for these therapies. And you need to - I'm happy to answer any questions about these therapies because that's a whole other can of worms.

What Else Can I Do for My Patients?

But you can also give your patient symptomatic therapy. So cholinesterase inhibitors are FDA-approved for dementia, mild, moderate, and severe. Not approved for MCI due to Alzheimer's disease, although some providers use those off-label. And memantine is only approved for moderate to severe dementia. So that's really important. There's no indication that it's helpful in earlier stages. You don't need to be giving it to your patients with MCI or mild dementia due to AD.

You can assess for progression to MCI to mild dementia. You don't need to wait for a neurologist or cognitive specialist to do that. And so these are really the standard treatments, the bread and butter of - for patients with Alzheimer's disease.

Treat the Whole Patient and Family, Not Just the Brain

You want to - in many ways, I think of the family as my patients too. So there's a lot of safety assessment, a lot of counselling that goes on telling people about the Alzheimer's Association. There's a 24-hour hotline that's at the very top of the website, which is alz.org. So no question - I tell my patients no questions too big or small, just call them anytime. They have social workers on the call on the line. So if it's 3:00 and you're, you know, at wits end, you - you have somebody you can call planning for the future, including estate planning, and then talking to the caregiver about caregiver burnout.

So I spend a large percentage of my visit talking about a lot of these factors including supervision, driving and so forth.

Rationale for Clinical Trials in Prevention

And so, as I was mentioning, there are a lot of clinical trials that are ongoing now looking at prevention of symptomatic Alzheimer's disease, because you have these silent brain changes occurring in preclinical AD. And so they’re - you know, the first trials have been negative, but they're now using new therapies that lecanemab is being tested, donanemab is being tested. So we'll see whether those trials bear any fruit.

Current Clinical Trials for Prevention of Symptomatic AD

And there are a number of ongoing trials for - for symptomatic therapies. So it's important to gauge your patient's interest and their family's interest in clinical trials. You can always check for up-to-date trials using clinicaltrials.gov, but I - you know, that's a standard part of my care. I refer many of my patients for ongoing clinical trials.

Current Drug Development Pipeline for AD

And it's an exciting time. So I want to leave you with this positive note that we are developing this pipeline for - these are all ongoing trials, all ongoing studies at the moment, and they target a number of different mechanisms. So it's not just amyloid. Some of these drugs are looking at epigenetic risk factors, synaptic plasticity, tau-based drugs.

Many of these drugs, 73%, are potentially disease-modifying therapies, which means they're going to change the slope, change the trajectory of the disease. And so we'll be hearing about the results of these studies in future years. But it's a very exciting time for the field. We all hope that these anti-amyloid antibodies are the beginning of a promising future in therapeutics and not - not the end.

So I think we have time for a couple here. So what differentiates normal cognitive aging from very early MCI in the geriatric population?

So to diagnose MCI, you want to establish that they have subjective concerns either from the patient or the people around them. Very often at this level of MCI, it's from the patient directly. And then you also want to establish that they have objective impairment when you test them in the clinic. So they - they need to demonstrate, for example, that they have memory impairment or language impairment or executive impairment or visual spatial impairment.

So those who are - have normal cognitive, aging will do just fine on those cognitive assessments.

Question - so that's a great question. Thank you for asking that.

Question two, how do you integrate family history, particularly maternal versus paternal into individualized AD risk communication?

So the area where family history is most important is when you have somebody presenting with symptoms before the age of 65, because you want to see whether you're hearing an autosomal dominant pattern of - of dementia, meaning that it's in every generation. So it could be on either side. It could be, you know, my father had it, my father's mother had it. You know, my - and so on and so forth. Or, you know, there or four of my mother's sisters had it, that kind of thing. So it doesn't - it's not that it needs to be on the maternal or the paternal side because these are all - these rare conditions are all autosomal dominant, but it comes into play when people present with symptoms before the age of 65.

Otherwise, you know, if you don't get that kind of clear history and you're not - you haven't - you're not considering genetic testing because they're over the age of 65 or you don't get that history, then, you know, what it means is that this patient's index of suspicion is higher. And they may be more aware of their symptoms coming into your clinic.

But, you know, if you can - it can guide your differential diagnosis. So, you know, I had a patient who came in and had a strong family history of Huntington's disease. And so then that - you know, that changed my differential diagnosis based on that.

Based on the ATN biological framework, how do you approach patient counselling when biomarkers are positive, but symptoms remain minimal or absent?

So there's a little bit of debate in the field about this. So in the ATN biological framework that was published by the Alzheimer's Association, they are now entering the early stages of preclinical Alzheimer's disease. But the international working group said that you should not call this Alzheimer's disease. Regardless, you know, I wouldn't get these biomarkers in people who are asymptomatic unless they are doing it as part of a clinical trial.

And even then, I would do it, you know, in the setting of that trial. Not in your - in the clinic setting because you want to have a pre-test probability that you think that they have Alzheimer's disease if you're getting AD biomarkers or Lewy body disease, if you're getting alpha synuclein biomarkers.

So you want to establish that pre-test probability. If you're not establishing that they have cognitive impairment in your clinic, I would not seek out these biomarkers. That may change if one of these preclinical trials is positive and our practice changes but for now.

Does tinnitus cause brain issues? It's not directly - so there are patients who have tinnitus and also present with cognitive concerns, but it's not that tinnitus causes neurodegenerative disease, or that tinnitus is a risk factor for Alzheimer's disease or other neurodegenerative conditions. But yes, those patients can report cognitive concerns.

Are certain psychiatric diagnoses more strongly associated with elevated lifetime risk of AD? So it's not that specific ones. So, you know, we know that people who go on to develop AD are at increased risk for depression and anxiety. And we know that there's this potential bidirectional relationship. There's also been a bidirectional relationship, not with the psychiatric diagnosis, but with loneliness. This idea that if people are lonely throughout their lives, it increases their lifetime risk of AD.

But - but other psychiatric diagnoses can increase your risk of cognitive impairment in general, not AD in particular. So for example, schizophrenia or schizoaffective disorder can be accompanied by a late life - by late life executive dysfunction, for example. But it's not that specific psychiatric diagnoses are more specific for elevated AD risk.

What proportion of MCI cases are preventable with risk factor modification? So, you know in the Lancet Commission report, they were looking at dementia risk specifically. And in that case, you know, risk factor modification could account for 45% of dementias, but that - that value is less clear for MCI cases. It may be somewhat similar because it's, you know, similar underlying neuropathology, but we don't have an exact number in the literature. But it may be something along those lines.

Does buspirone help to reduce the issue? You know, I - do you mean reduce risk of dementia? Unfortunately, it hasn't been shown to reduce dementia risk. But that would be wonderful if it did. We don't have that evidence at this point in time.

And then the final question here. All of these are great questions by the way. Thank you so much for your participation and your insightful questions. How do you choose between PET CSF or blood biomarkers as diagnostic tools? Great question there.

So if I - if I've determined that somebody has MCI due to AD or mild dementia due to AD and I'm considering anti-amyloid therapies, then I will often get either an amyloid PET scan or CSF testing. And I get the CSF testing when I want to establish their tau status.

Maybe the diagnosis isn't - because it's really the tau protein that's most associated, most correlated with cognitive impairment itself. As I mentioned before, amyloid protein can start to accumulate decades before. So just because somebody has an - an - an - an abnormal amyloid PET scan or abnormal amyloid-based biomarkers doesn't mean that they have symptoms of Alzheimer's disease.

And so - so I will get the CSF testing when I'm - I'm interested in the tau value. I really want to be certain about the AD diagnosis. But if the clinical picture really fits with Alzheimer's disease, then I may just get the amyloid PET. And then if they're appropriate candidates, start them on anti-amyloid therapies.

In patients who are not candidates for anti-amyloid therapies, for whatever reason, maybe they have ongoing cancer, they're on anticoagulation, whatever the case may be, then I might get a blood-based biomarker instead. Or sometimes the blood biomarker, because it's so easy to get and it's cheaper, can be an initial screen. And if it's negative, you stop there.

But if it's abnormal or elevated, you might get one of these ancillary tests like an amyloid PET scan as additional confirmation. Or generally, these blood-based biomarkers will have two cut-offs and there's a sort of an intermediate zone. And so if they're in that intermediate zone, then additional biomarker confirmation with the PET scan can be helpful.

So that's, you know, a whole other encyclopedia. But I hope I can give - that gives you a little bit of - of a sense of how I think about these different biomarkers.

So thank you all so much for your attention. It was a joy to be here. Thank you for your questions and I appreciate your time today. Take care.