Hello and welcome. My name is Dr. Raj Tampy, and I'm the professor and chairman of the Department of Psychiatry at Creighton University School of Medicine in Omaha, Nebraska. I'll be serving as your moderator for today's webinar titled, Updates on Diagnostics and Therapeutics for Alzheimer's Dementia. We are thrilled to have two distinguished speakers join us today, Dr. Ganesh Gopalakrishna and Dr. Pallavi Joshi, both geriatric psychiatrists from Banner Alzheimer's Institute and the University of Arizona College of Medicine in Phoenix. Before we begin, let me briefly introduce our esteemed speakers. Dr. Ganesh Gopalakrishna is a board-certified geriatric psychiatrist and dementia specialist at Banner Alzheimer's Institute. He completed his psychiatry training at the University of Missouri-Columbia, where he also earned a master's in health administration. Afterwards, he pursued a fellowship training in geriatric psychiatry at Vanderbilt University. Dr. Gopalakrishna has published extensively on topics such as administrative psychiatry, schizophrenia, and dementia, and currently serves as the associate program director for the Geriatric Psychiatry Fellowship Program at University of Arizona, Phoenix. In addition, he is the clinical director of Banner Alzheimer's Institute, where he specializes in multidisciplinary dementia care for patients and their families. Our second speaker is Dr. Pallavi Joshi, who is also a geriatric psychiatrist at Banner Alzheimer's Institute in Phoenix, Arizona, and clinical assistant professor of psychiatry at the University of Arizona College of Medicine, Phoenix. Dr. Joshi serves as the program director for the Geriatric Psychiatry Fellowship Program at the University of Arizona. Dr. Joshi completed her geriatric psychiatry fellowship at Yale School of Medicine and completed her residency at Northwell Health, Staten Island University Hospital, where she served as chief president. Dr. Joshi has held leadership roles in several prestigious psychiatric associations and has presented at numerous national conferences on topics in psychiatry and geriatric psychiatry. Dr. Gopalakrishna, next slide, please. CMA credits. Today's webinar is designed for 1.5 AMA PRA Category 1 credits for physicians. Participation credits will be available for 60 days following today's session. Next slide, please. For today's presentation, captioning is available. To enable, click Show Captions at the bottom of your screen. For a full transcript, click the arrow and select View Full Transcript to open captions in a side window. Next slide, please. Please feel free to submit questions at any time by typing them into the question area located in the lower portion of your panel. We will dedicate the last 10 to 15 minutes of the presentation to answering your questions. Next slide, please. Okay, so now it's my time to hand it off to Dr. Gopalakrishna. Please, thank you. Please, thank you all for joining us. Dr. Gopalakrishna. Thank you, Dr. Tampey. Thanks for the introduction and we will just dive in in the interest of time into the topic of introduction to Alzheimer's. So in my section of the talk, I'm just going to give like a foundation of what these terminologies mean with dementia, mild cognitive impairment. We'll also define the continuum of Alzheimer's disease. We'll go kind of back and forth in these two topics. Then we'll dive a little bit into how frequent is Alzheimer's disease? What are some of the things that contribute to it? What is the neuropathology that you can see with Alzheimer's disease? We will get a pretty good view of the biomarkers that are used currently and the prospective ones in the future. And we'll also spend some time in the revised criteria in management of Alzheimer's disease recently published this year. I'm going to start off with this slide. And my intention here is to kind of distinguish what is normal aging and what is a typical disease process for a neurodegenerative disease. It says the continuum of Alzheimer's disease, but you could put any neurodegenerative disease in this and would have kind of a similar pattern here. So the solid black line here represents normal aging. So you do see some cognitive changes. It kind of denotes a decline, but I would like to think about this as changes. There is some cognitive changes that happen with aging itself. But it is not very substantial and does not interfere with someone's ability to function independently. Someone with a neurodegenerative disease such as Alzheimer's disease will have this extended period of time called the preclinical phase, which we will talk about more in detail later, where there are no symptoms, but there are changes that are happening in the brain over time. And this could last years and sometimes even decades for these changes to be enough to cause symptoms. And then that kind of leads into this phase of mild cognitive impairment, which eventually leads to dementia and there is a progressive decline over time, and this takes years again. Now, I'm going to start off with dementia, which is that last stage, just so that we kind of know what the distinctions are. So we identify dementia as a clinical term or a diagnosis where people have cognitive symptoms, which are a significant decline from previous levels of their cognitive functioning. And they also interfere with their ability to work or complete their IADLs or instrumental activities of daily living or, you know, be able to function independently. So when they have both cognitive decline and functional decline, we call that as dementia. And this should not be explained by, this should not be diagnosed in the context of a delirium or a major psychiatric disorder. There's also, you know, we quantify cognitive impairment based on subjective reports or objective observations from the family or even objective cognitive assessments. So we'll have to have both, you know, concerns and an objective cognitive assessment. And now we're going to go into this gray zone that we saw on that curve, which is just before the dementia stage. This kind of, this mild cognitive impairment was conceptualized in late 1980s as a gray zone, as a transition zone from the preclinical phase to dementia. Initial kind of focus was to identify patients with early Alzheimer's disease, but eventually we figured out that there are patients who have other types of dementia who have kind of similar presentations of mild cognitive impairment. The estimates are that it affects about 8 to 10 million Americans currently. So in this, the criteria is that there is a change in cognition. There may be a moderate decline in someone's cognitive abilities, which is different from their previous levels. And they're noticed by the patient, they're noticed by the family, and we can also substantiate with cognitive testing, but it is not severe enough to affect their day-to-day functioning. So their functioning capacity is largely impaired. And this is kind of becomes tricky sometimes as to how to determine those functioning impairments. But in these patients, you know, complex tasks can be slower. People take more time and it may take more effort in completing these tasks, but they're still independent in doing these tasks. And they need very minimal assistance from their family to be independent. So generally, about prognosis-wise, about 10 to 15% of these patients will progress to dementia every year to two years. But not everybody progresses to dementia. About 10 to 15% may stay where they're at, or rarely they may even revert back to an unimpaired stage based on the etiology. But if it is related to a neurodegenerative disorder like Alzheimer's, they're almost always likely to progress over time. So it's really hard to prognosticate at an individual level as to how a person is going to progress over years, but it helps to give a broad picture and also emphasize the need for us to monitor over time and involve them in decisions about what their care should look like once the disease progresses. Now we're going to club both of them, dementia or mild cognitive impairment, can be caused by a lot of different disorders. So this is a kind of an arbitrary distinction with reversible or treatable conditions and neurodegenerative conditions on the right side. But sometimes it's not completely reversible, even if it is related to one of these causes on the left column. So depression and anxiety can cause cognitive impairment along with severe stress, occupational burnout, especially later in life. Obstructive sleep apnea is one of the most common things that we address when we are assessing patients for cognitive impairment. Metabolic disturbances like vitamin B12 deficiency, hypothyroidism can present with cognitive issues, exposure to toxins, excessive alcohol use, infections, brain, space occupying lesions like meningiomas can also present with cognitive issues. And is the reason why we do a basic workup for everybody to rule these things as potential causes. And once we rule those things out, we get into the neurodegenerative disorders as potential reasons. And the most common disease in this category is the Alzheimer's disease. And we'll get to the numbers in a little bit. But the others are vascular dementia, Lewy-Barr disease, frontotemporal dementias. And oftentimes there is a mixture of these two, like mixed etiology is quite common, especially as you grow older. And the less common reasons why people have dementia include PSP, CJD, corticobasal degeneration, normal pressure, hydrocephalus, and others. So here's kind of the breakdown of all types of dementias. Alzheimer's, of course, you can see this big orange block that almost contributes to about 60% to 80% of all-cause dementia. You know, there are some people with vascular dementia, which is about 10% to 20%. But of course, there's a lot of overlap between these and another 5% to 10% of Lewy-Barr disease. But you can see this big block in between the Lewy-Barr disease and vascular dementia, which is mixed dementias, which show features of more than one pathology when they look at the brain's postmortem. And frontotemporal dementias are less common after the age of 65. And that's where Alzheimer's disease predominates in these situations. Now we'll get into Alzheimer's disease itself. So it's the most common type of dementia, as we mentioned. And that's, by the way, one of the most common questions we have, is this Alzheimer's or dementia? And what is the difference that you have? Dementia is a syndromic diagnosis and Alzheimer's is a pathological diagnosis. An estimated about 6.9 million Americans are living with Alzheimer's right now. And it's the fifth leading cause of death, which kind of went up and down when COVID was in full swing. But it's one of the leading causes of death in the U.S. And it really disproportionately affects women. And it affects women in a way that they are more likely to have Alzheimer's disease because two-thirds of the patients with Alzheimer's are women. But they're also more commonly the caregivers too. So they get affected on both sides. There's also some racial disparities in how this plays out. Non-Hispanic black and Hispanic older adults are more likely, about two to three times more likely than white older adults to have Alzheimer's. There's plenty of other, plenty of hypothesis and reasoning why this happens. But the cardiovascular comorbidities are one of the leading causes, leading reasons why there is this disparity. And of course, there is disparities in education levels and socio-demographic disparities that play into this. So this is a less known fact, and this is kind of really surprises a lot of people. Even though the numbers of Alzheimer's disease patients are going up, the prevalence and incidence of Alzheimer's and other dementias in the U.S. and other high-income countries have actually declined over the past 25 years. And the most common reason why people believe this happens is because the education levels have gone up over the decades. And we have done a better job in controlling risk factors like high blood pressure, diabetes, high cholesterol, traumatic brain injuries. We've been able to avoid some of these bad things that we are able to actually reduce the incidence and prevalence. But just because we have an aging population, the numbers are going up and estimated to go up even further. So I'm just going to give you a snapshot of how well we take care of this disease. We don't do a really good job at this. You know, up to 30% of the people 65 and older are estimated to need a geriatrician. But if we need to meet that requirement by 2050, we have to really increase our geriatrician workforce by nearly nine times. It's not really feasible. Kind of similar things that would apply to neurologists and geriatric psychiatrists. We know this is a big problem nationally. You know, increasing the number of APPs and social workers may help, but still the significant care gaps are prevalent even now and estimated to continue to grow as we have an aging population. You know, we cannot really afford people to see dementia specialists all the time. 85% of the people with dementia were diagnosed by providers who are not specialists. And, you know, we don't have enough specialists to go around to diagnose every person with dementia. And it's sometimes or oftentimes it's delayed until a moderate or advanced stages are identified or diagnosed in 50% or more cases. And this is especially magnified in patients with racial disparities, like, you know, with racial and ethnic minority groups. And people who do take care of these patients are not really adequately prepared to take care of them. It leads to a very high fragmented care model in the society. It's a very expensive disease to manage. And you can see that this is, as of 2024, the total cost is about $360 billion. And this does not include informal caregiving support. This is just Medicare, Medicaid, and out-of-pocket expenses that come into account for $360 billion a year. Now, let's get into why this happens. I want to kind of divide up the risk factors into two categories, the non-modifiable risk factors, not something that you can change. The age is the biggest risk factor in this category. You can see on the right side, the risk of having Alzheimer's disease, the incidence goes up from 5% between 65 to 75 to 13.2 and almost to 35% at more than 85 of age. So there are some studies which will show that at age of 85 and above, the risk of having Alzheimer's is one in two or one in three people. So age is definitely the most consistent predictive factor or a risk factor for Alzheimer's disease. Family history is also important. If you have one family member, like a close biologically related family member having Alzheimer's disease, your risk goes up to some extent. And if you have that, this goes up even further. And genetics also plays a big role in this. And we want to look at this in two ways. So people who have symptoms after the age of 65 were categorized as late-onset Alzheimer's disease. APOE4 is a significant gene of interest for us. So everybody has APOE genes. These are involved in lipid metabolism and transport. And there are three alleles, 2, 3, and 4. So the APOE4 allele tends to confer risk on people who possess them. So if you have one copy of the APOE4, your risk goes up two to four times compared to not having the gene. If you have two copies of the gene, your risk goes up eight to 10 times compared to someone who doesn't have this gene. In early-onset Alzheimer's disease, these are the people who have the symptoms before the age of 65. Presenlin 1, Presenlin 2, and APP gene tend to be the most common genes to cause these early-onset disease. But again, they only account for about 10% of all these patients with early-onset Alzheimer's disease. Majority of them are sporadic in nature. But these genetic factors can increase amyloid production and cause Alzheimer's much earlier in their lifetime. And Down syndrome is of interest because it's a trisomy of 21. So the APP gene, which is the amyloid precursor protein gene, exists on the 21st chromosome. So they have more production of the amyloid protein. And virtually all individuals with Down syndrome have sufficient AD pathology to meet pathological criteria by their mid-40s. And now moving on to the non-modifiable risk factors, which we think attributes to about 40% of the risk for the disease itself. The biggest one is physical activity, and this pertains to physical activity even in midlife. A good amount of physical activity tends to delay the onset of Alzheimer's or reduces the risk of Alzheimer's. Education, people who have a college-level education are at a lower risk compared to high school-educated or less than high school-educated people to have Alzheimer's disease. People with a cognitively-driven job, like a white-collar job, tend to have a lower risk of Alzheimer's compared to someone who's doing construction work, which does not include so much of the cognitive processing. Diet has shown to be very effective here too. So a MIND diet or a DASH diet. So these are Mediterranean diets. Not both of them are Mediterranean diets, but Mediterranean diet, DASH diet are all focused on less red meat, more white meat, more vegetables and fruits in the diet, more antioxidant type of diet has shown to be more effective. Anything that is heart-healthy is conceptualized to be brain-healthy and has a lesser incidence, lesser chance of having dementia. Social and cognitive engagement, again, throughout their life improves the chances of not having so much of a cognitive decline later in their life. Adequate sleep is shown over and over again to be a good thing to do throughout the life. I believe that the amyloid clearance happens during the sleep. So when people are sleep-deprived, there is more accumulation of amyloid. There's also good correlation between having obstructive sleep apnea and dementia later in life. Hypertension, diabetes, hyperlipidemia are all vascular risk factors that increases your risk of dementia along with obesity. Smoking also belongs to this category, increases your risk. People with a history of significant traumatic brain injury are at a higher risk of having dementia. And air pollution was recently added from this Lancet group in the risks that contribute to dementia. Neuropathology, what happens actually in the brain, we believe the leading hypothesis for Alzheimer's disease is the amyloid hypothesis. We believe that the amyloid starts accumulating extracellularly decades before the onset of symptoms and they aggregate, they become sticky, they start aggregating together and they cause synaptic dysfunction. And eventually those are the plaques that is outside of the brain cells. And eventually the tau protein, which is an intracellular protein, starts misfolding and starts affecting the axonal flow within the neurons and causes neurodegeneration. And that spreads across the brain. Along with this, there's also inflammation that's going on. There's also plenty of evidence to suggest that it's astrocytes and synaptic dysfunction, eventually leading to shrinkage of the brain and not able to function well. So we want to get into biomarkers now. And the biomarker, so with the biomarker, we are trying to identify a test which can kind of tell us if this, if it correlates with the disease process that's going on. And we want to have, for Alzheimer's disease, so these are specific to Alzheimer's disease, a biomarker needs to have a strong correlation with the PET amyloid. So this is a PET scan to look for amyloid in the brain and also PET tau scans, which is looking for tau in the brain. We want to have good correlation with it because that's kind of like the gold standard for us for diagnosis. We also want to be able to use a biomarker which can differentiate Alzheimer's disease from non-Alzheimer's disease dementias. So this is pretty challenging clinically. So even, you know, in specialist centers like ours, the accuracy is close to like 70%. We think that it is Alzheimer's, but when they do an autopsy, it is something else. So we want to be able to identify a biomarker which can distinguish Alzheimer's from a non-Alzheimer's pathology. And we also want to differentiate with a biomarker people with Alzheimer's dementia versus a non-Alzheimer's mild cognitive impairment so that we are able to prognosticate better and also initiate treatments early enough. If you know, we also want to identify a biomarker which can predict who is going to progress from mild cognitive impairment to dementia. You can recall from the past, we were not really great in prognosticating at an individual level, but if a biomarker can do that for us, that'll be great. And also we want to identify patients at risk of who is going to develop amyloid positivity. And, you know, we are now at a point where we have some tests which can identify who is going to convert to being amyloid positive over time. So when we look at biomarkers, we want to think about fluid biomarkers and imaging biomarkers. And there's also some interest in digital biomarkers, which I'm not going to go into much of details. But the fluid biomarkers, we want to think about doing these tests on the CSF. So we do a lumbar puncture, get some fluid, and we look at the biomarkers in the CSF. And we'll see what specifically happens, but we generally rely on hybrid ratios like A-beta 42 by P-tau or A-beta 42 by 40 ratio. So those are the type of things that we'll be looking into. But blood-biased biomarkers are something that you can just do a blood draw, look for these biomarkers. So this is really the exciting part of our field now. And these can be used as a standalone. We don't need to do ratios on these. And imaging biomarkers are things that, you know, are going to be measuring things which are cumulative effects, things that have happened over the years. It's not like a snapshot, like fluid biomarkers. This is going to demonstrate what are the neuropathological changes that have accumulated over time. And these can include neuropathological imaging biomarkers, like we can do a PET scan looking for amyloid in the brain or the tau in the brain. Or we can look at neurodegeneration, which is a downstream effect, using MRIs or PET-FTGs. The PET-FTG is a metabolic scan. We give a dye and see which parts of the brain is metabolically active. And that can give us the ideas of like which part of the brain are not working well. And that pattern can be very useful diagnostically. Now we are going to take one part of that. That's the blood-based biomarkers. And it's similar with the CSF biomarkers. So we are just going to take blood-based biomarkers for the sake of discussion here. Generally, what we see with CSF or blood is that the amyloid Aβ42 levels go down. So you can see on this pictorial representation, we expect the Aβ42 levels to be low in patients with Alzheimer's disease. The hypothesis is that all of this is being accumulated in the brain. So the levels peripherally is low. So a lower Aβ42 by 40 ratio aligns with amyloid deposition and with the amyloid PET being positive. So that's kind of the indicator of Alzheimer's disease. On the other side, the p-tau levels go up. And the p-tau just stands for phosphorylated tau, which we'll go over in the next slide. There are some challenges using amyloid beta measurements in the blood, especially. So there is less fold change, which means like when I measure it today and I want to measure it again in six months, the change from today to six months may not be twofold or threefold. So it's slowly progressing. So it is harder to make that measurement and make sense of serial measurements and to identify thresholds. There has been a lot of concerns about the assays, but they are getting better and more reliable. But still, we are not there yet to have like a reliable Aβ42 plasma assay. There are some in the community, but those are the challenges with those. On the other hand, the phosphorylated tau, we believe that the tau protein, which is a normally occurring exoskeleton protein within the neurons, gets phosphorylated in specific areas. We think that this correlates really well with the time the amyloid start depositing. So there are three biomarkers of interest, the p-tau 181, 217, and 231. So there is very good evidence that there is good correlation between CSF levels of these p-taus and the blood levels. So that is a very big step in our field because we don't have to be invasive and looking for CSF. If we are able to get that on the blood, that's great news for all of us. And levels start increasing close to amyloid positivity in the PET. So we think about these closer to the amyloid deposition. And levels start to increase just after the ratio goes down and prior to cut off on the amyloid PET. So it's just that window and we'll go over that in a little bit. So the good thing about the p-tau is it's able to deliver on all those biomarker characteristics that we were hoping for. It can detect Alzheimer's disease pathology. It can identify people with preclinical AD staging. We can do this, we can stage patients clinically, and we can potentially track treatment efficacy. So there are a couple of tests commercially available, but they're not FDA approved. And this is going to likely get into our clinical practice quite a bit. So I'm going to go through this quickly. So there are other biomarkers of interest. Glyal Fibrillary Acidic Protein or GFAP, which is a glyal marker. Plasma levels correlate with CSF, but they're not specific to AD. The Neurogranin level is another biomarker elevated in Alzheimer's disease, but they don't really correlate well with the plasma levels. So because we have other markers, this is kind of lost favor. There are some nonspecific markers of neurodegeneration, which means that the brain is kind of degenerating, but it is not specific to Alzheimer's. So these are Total Tau and Neurofilament Light. Now we'll get into the staging criteria for Alzheimer's disease. So this is a work group that was put together, and they have kind of provided recommendations from 2011 and then 2018, and they've had revisions over time. So this is kind of their process. I'm going to skip to the next slide and come back to this one. So this is their fundamental principles to where they started. They wanted to define Alzheimer's disease as defined by its unique neuropathology, which is that plaques and tangles, so amyloid and tau. So they also identify that they are able to detect Alzheimer's disease pathological changes by biomarkers, and that's good enough to diagnose the patient itself. And they also wanted to focus on this Alzheimer's disease being on the continuum in the clinic. So it starts in the preclinical phase, goes to the mild cognitive impairment phase, to dementia, and in stages of dementia too. So it exists on the continuum. The symptoms are results of the disease process and not necessary to diagnose Alzheimer's disease. So they wanted to take an approach of a neuropathological diagnosis rather than a clinical diagnosis for Alzheimer's. So people who are unimpaired individuals with abnormal biomarker results are at risk of symptoms due to Alzheimer's, but they already have the Alzheimer's. They're not at risk for the disease, but they are at risk of having symptoms in the future. So these are the kind of the fundamental principles they wanted to pursue. Now with that as a background, so they wanted to have this integrated biological and clinical staging. So we'll go over like how they staged it biologically and clinically in a little bit. But they also wanted to factor in copathologies, cognitive reserve, and resistance as to how they modulate some of these presentations in an individual person, in an individual. So the Alzheimer's disease, they defined as a biological process that begins with the appearance of AD neuropathological change, that is this ADNPC, while people are asymptomatic. So once they have the biological process started, they have the Alzheimer's disease. And they identified these core one biomarkers, which show that either beta amyloid or AT tau pathway has initiated and reflect the presence of AD neuropathological change. So with that being said, one abnormal core one biomarkers is sufficient to establish a diagnosis of Alzheimer's disease. They just need to have one evidence to show that this amyloid pathway or the tau pathway has been initiated to diagnose someone with Alzheimer's disease. They don't have to have any symptoms. And later changing core two biomarkers can provide more prognosticating information and will, in abnormal, it also increases your confidence that AD is contributing to these symptoms, but they are not required for making a diagnosis. So here's where we will start with this. So the lavender kind of line, the first line is where we start seeing the CSF A beta 42. And we are kind of saying that, you know, and there is a small gap between the CSF A beta 42 and the amyloid being positive here on the red line. So the P tau levels are somewhere in the middle where they can get positive. And there is, and you can see the green shaded areas where the symptoms start happening. This is an older kind of curves from Jack, but they're still pertinent here. These green shaded areas where the clinical symptoms are happening and the tau levels, which are kind of on the blue line, tend to correlate the best with the clinical progression of the disease itself. So here is the gist of all the biomarkers. So we're, as you may recall, the core one biomarkers is what we need to just make a diagnosis of Alzheimer's disease. And that those are the ones that are going to be the early biomarkers that show up in the disease process. So those are again categorized into amyloid related proteinopathy. So amyloid proteinopathy, which is the A beta 42 and the CSF for plasma, or it can be an amyloid PET. The tau related thing is to the P tau 217, P tau 281 and 231. Though they are kind of related to the tau pathology, they're not, I mean, they don't really relate to that the tau is spreading in the brain, but these are more correlated with the amyloid deposition in the brain. So that's why they're put in the core one biomarkers. And you know, the timing is kind of different between these, each of these biomarkers, as we mentioned previously, the core two biomarkers is where the tau pathology is already spreading. And these are the MTBR tau 243 or other phosphorylated tau like P tau 205 or a tau PET. The reason why they make this distinction between core one and core two is patients don't need a tau PET to make a diagnosis of Alzheimer's. So the core one biomarkers are adequate and they are early in the disease process for us to detect and make a diagnosis of Alzheimer's disease. And there are some nonspecific processes that involve that you can detect too. So that's one is the neurodegeneration or N, the injury dysfunction that happens. So you can detect that by a neurofilament light or doing an MRI and showing that there is degeneration or shrinkage of the brain atrophy in the brain or PET-FTG like we discussed before. There's also astrocyte activation that is nonspecific to Alzheimer's and you can detect that with the GFAP. And you can also do other biomarkers for non-AD co-pathology and rule them out. If you say, you know, there's no alpha-synuclein or no infarction on the MRI or CT, then you're ruling out other co-pathologies, but they are not biomarkers specific to Alzheimer's, but you're ruling out other pathologies. So here's kind of another loaded slide and the purpose here is to kind of show like what all you can use. So for the stage of diagnosis, and this is divided in the clinical stages so for your clinical use, for the stage of diagnosis, you want to use an amyloid proteinopathy indicator, so that can be an amyloid PET, or you could do a p-tau-217 to identify patients who have Alzheimer's disease. And you can also use hybrid ratios like p-tau-181 by a-beta-42 or total tau by a-beta-42 or a-beta-42 by 40 ratios. So any of those things can be used in the diagnosis. And as the disease progresses, or even if you want to stage the disease and identify where they are, you could use an amyloid PET again, p-tau-217. And here's where you start getting the tau measures like the MDPR tau-243 or the tau-PET to see if they have gone to the point where they're going to start having symptoms soon. And you can also use the GFAP to assist your diagnosis or prognostication. Here's kind of a breakdown of the stages. So this is the neuropathological stages of the disease. So they've divided into A, B, C, D. And we'll see how this correlates with clinically in a bit. But stage A, you just have the amyloid PET positive, but the tau PET in the medial temporal lobe or the neocortex is all negative. In stage B, you start having some tau PET in the medial temporal lobe. Stage C spreads to the neocortex, which is kind of this tau spreading across the brain. And stage D is where you have high tau presence throughout the brain. And this kind of correlates with the high level of, I mean, advanced stages of dementia. So again, to reiterate, plasma I, core I plasma assays can establish that a person is on a biological stage A or higher, but cannot discriminate between PET stages A to D at present. So you will have to do one of these other things to say, well, staging of the disease. So amyloid PET can only diagnose if they have the AD pathology. So with that, there is also the caveat that you always want to use clinical judgment because you may have someone who has more than one pathology that's going on. So someone may have Parkinson's disease and they may have an Alzheimer's, which is just brewing in the background. So they may have an abnormal PET, but if the Parkinson's disease is the most prominent thing, then AD is not the dominant pathology. You also may have some discordant biomarkers. So sometimes the P tau is elevated, but the AB to 42 is not elevated. So in those cases, additional testing may be required. And there are some confounding conditions which may affect P tau levels like history of head trauma, cardiorespiratory arrest, impaired renal functions, and there are other scenarios too. So you will have to factor in if those are causing some of the elevations in P tau levels. So here is the clinical staging of Alzheimer's disease, and they want to bring both those things together, integrating the pathological and clinical staging. But clinically, they want to identify this as something new. So they want to identify this stage zero where people are asymptomatic, but they have genetic predisposition. They don't even have biomarker evidence. So there is no really syndromic correlation here. But then stage one are these patients who are asymptomatic, but there is biomarker evidence of Alzheimer's disease. And these are the patients we call as preclinical Alzheimer's disease. And stage two are people who have mild detectable changes, like the patients are perceiving it, or maybe people around them are seeing changes, but there are not really any objective evidence to show that they have had a decline, and they may have had minimal impact on daily functions. So these kind of closely correlate with subjective memory complaints or cognitive decline as a diagnosis. Then it proceeds to people with cognitive impairment with early functional impact, but still independent in functioning. These are people with mild cognitive impairment. And then it goes to people with mild functional impairment, which correlates with mild dementia, moderate functional impairment, which is moderate dementia, and severe functional impairment with severe dementia. So that's stage zero to six clinically that they have identified. So you got the A through D on the neuropathological side and zero to six on the clinical side. So some of the things that you want to be aware that, you know, right now there are no biological treatment, no biologics available for prevention. You will see Dr. Joshi's presentation that we have it for the mild cognitive impairment onwards, but we don't have anything for prevention at this time. So it is not recommended for screening asymptomatic individuals. So if someone walks in and says, I want to get screened for Alzheimer's, it's not really recommended at this time because, you know, it has psychological burden knowing this disease and without any treatments available, there's not really a clinical indication here. And you also want to search for other contributors that may be affecting the cognition. And in some patients you may want to consider symptomatic treatments. So in summary, Alzheimer's disease exists on a continuum from asymptomatic to severe dementia. Remember that clinical staging zero to six. Alzheimer's is a common disease, affects a lot of older adults disproportionately in the U.S. and globally. These revised criteria focus on biological construct and says that the Alzheimer's disease starts at the time of amyloid deposition, not at the time of symptom onset. The clinical stages integrate with it. There are excellent biomarkers that are available and will be soon used in clinical practice routinely. And that's going to be a significant paradigm shift for us. Okay. With that, I will stop here and I will let Dr. Joshi take over. Thank you, Dr. Gopalakrishnan, for that excellent introduction. I'm Dr. Joshi and I'll be talking about the pharmacological management of Alzheimer's disease. Next slide, please. So the treatment paradigm for managing Alzheimer's disease combines pharmacological and non-pharmacological approaches to mitigate the progressive loss of cognitive and functional abilities. There is no way to halt or reverse the progression. So the treatment approach is to try to mitigate it. And the pathological processes that Dr. Gopalakrishnan underlined begin several years, even decades before the clinical symptoms start to manifest. So the disease has been present for a long time before we can even start to diagnose or treat it. And it occurs at multiple levels of destruction, molecular, intracellular, cellular, and systems. And so the treatment aims are to retain the quality of life, to mitigate the burden of illness, and to reduce the long-term clinical decline. Next slide, please. So regardless of the treatment interventions, AD has a progressive course. So it can be difficult to know whether a medication is working or not. It's difficult to know whether a medication is slowing down the progression more than what it would have been without the medication. And so the treatment expectation with these medications is not an absolute improvement or a reversal of symptoms, but rather an improvement compared to what the condition would have been like in the absence of treatment. So a lot of times patients or families start colonoscopies and feel like patients are not getting better and they're not getting better, but the medication is doing something at the molecular and cellular level to delay the progression. And so if they're tolerating the treatment, they're not having side effects, then they would continue the medication because over the long run it almost always results in an improvement compared to the progression that might have been without the medication. Next slide please. So cholinesterase inhibitors are the first line treatment for the management of Alzheimer's disease. Donepezil, rivastigmine, and galantamine are the three main ones, and they all work via the mechanism on acetylcholinesterase, inhibiting the breakdown and thereby increasing the amount of available acetylcholine in the brain. Next slide please. Donepezil is the most commonly prescribed. It's a highly selective, reversible cholinesterase inhibitor, and it's approved for mild to moderate AD. And it works by modulating the alpha-1 adrenergic receptors, but it also has other mechanisms like improving the neuronal plasticity, reducing core inflammatory cytokines, and also has decreased APP and excitotoxic injury. Next slide please. Rivastigmine is another reversible cholinesterase inhibitor that also works very similarly to donepezil. Next slide. And galantamine is also- Can I just interrupt? People are saying that, you know, your audio is a little fuzzy. Can you speak a little closer if possible? Thank you. Sorry about that. Is that a little bit better? It is better. Yeah. Thank you. Okay. Thank you. Okay. And galantamine was approved in 2000 as a reversible ACE inhibitor, which is a selective inhibitor on the CNS with little activity on the peripheral tissues. Next slide please. Okay. So this is just a brief table that summarizes the pharmacokinetics of these three medications. So as you can see, rivastigmine is also available in a patch form. The patch form tends to have lower GI side effects, and so it tends to be better tolerated by individuals who are more susceptible to the gastrointestinal side effects of these medications. And galantamine also comes in an extended release formulation. All of these are hepatically metabolized. Next slide please. In terms of dosage titration, donepezil starts at five milligrams once a day initially, and it can be increased to 10 milligrams once a day after four to six weeks if it's tolerated. The most common side effects are gastrointestinal, so nausea, vomiting, loss of appetite. Taking it after a meal in the morning helps decrease the risk of this side effect. So I always counsel patients to eat a full breakfast in the morning, something hearty like eggs and toast or oatmeal before taking the medication. And then other notable side effects to watch out for are bradycardia and hypertension. Rivastigmine comes in a capsule form, which is dosed twice a day, starting at 1.5 milligrams BID initially, and then increasing to three, and then finally six, twice a day if tolerated. The side effects are very similar to donepezil as well, and the transdermal patch, which comes in three different dosage formulations, has a lower risk of the GI side effects. However, the transdermal patch does have a risk of local skin irritation and reaction, and it is a 24-hour patch, so it does need to be changed every day. And finally, galantamine has an extended release capsule dosed at eight milligrams once daily for four weeks, and it can be tolerated, and it can be increased to 16 if it's tolerated, and then further to 24. And the immediate release tablet or solution is dosed twice daily. The side effects, again, are very similar to rivastigmine and donepezil. Next slide, please. Okay, so what does the literature show us about the evidence of donepezil? What does the evidence say about its efficacy? So in a conference review, which looked at 30 studies involving over 8,000 participants, donepezil had a marginal increase in benefits on the 10 milligram per day capsule compared to the 5 milligram per day capsule. So while the 10 milligram dose may be better for those who do not tolerate the 10 milligrams, they might do fine and are doing fine on the 5 milligram, they'll still get some, a lot of the benefit from the 5 milligram dose. However, the rates of withdrawal and adverse events are naturally higher with the higher doses. And over time, cognition was better as measured by the ADCS-ADL, and with the, and behavior, there was no difference between behavior, between donepezil and placebo. And same with the quality of life, there was no difference between donepezil and placebo and quality of life. Next slide, please. And this just shows the same clinical improvement in a graphical form. The difference in MMSC change from baseline starts to separate between donepezil and placebo at 12 weeks and becomes clinically significant at 24 weeks. And it's sustained at 52 weeks or the one-year mark. So at the one-year mark, people who were on donepezil performed much superiorly on the MMSC compared to those who were on the placebo. Next slide, please. And there's a similar review, there's a similar Cochrane review for rivastigmine of 13 trials with over 8,000 participants. And this looked at the capsule dose up to 12 milligrams and the transdermal patch formulations. And again, they found that cognition was better on rivastigmine as measured by the ADAS-COG and also by the MMSC. And again, they found no differences in behavior or quality of life between rivastigmine and placebo. Next slide, please. So Dr. Ganesh talked about mild cognitive impairment as a precursor stage. And what are the current guidelines for cholinesterase inhibitors and mild cognitive impairment? So the clinical benefit for cholinesterase inhibitors in mild cognitive impairments are inconclusive. Some studies have shown no benefit on the cognitive outcome or reduction in progression from MCI to dementia. And yet the side effects are common. So a lot of people will have gastrointestinal or cardiac side effects. So given the risk-benefit ratio, the recommendation is inconclusive. So the options are that first, if the clinician chooses to offer cholinesterase inhibitor, they must first discuss with the patient that this is an off-label prescription. Off-label does not mean that it's not going to definitively work or not going to have any benefits towards the patient, but it's important for them to know that the medication is not approved for this indication. And secondarily, if they are diagnosed with MCI, they may not choose to offer cholinesterase inhibitors. Now Dr. Gopalakrishnan also talked about MCI secondary to Alzheimer's disease versus other forms of dementia. If the MCI is not thought to be secondary to Alzheimer's disease, if it's thought to be secondary to a known vascular cause, if it's thought to be MCI secondary to alcohol use, then cholinesterase inhibitors will have minimal benefit because the neurobiology and the psychopathology of Alzheimer's disease, which is what the cholinesterase inhibitors work on, is not present. Next slide, please. Now we'll talk about Mimantine, which is a medication a different class from the cholinesterase inhibitors. It's a moderate affinity uncompetitive NMDA antagonist, and it's approved for use in moderate to severe AD. Its use in mild AD is off-global. Next slide, please. And it comes in two formulations, instant release and extended release. Both are renally metabolized as opposed to the cholinesterase inhibitors, which are hepatically metabolized. Next slide, please. The starting dose is five milligrams daily, and it's increased in five milligrams increments one week apart until the target dose of 10 milligrams twice a day is achieved at week four. Unlike cholinesterase inhibitors, it doesn't have significant GI side effects like nausea, vomiting, diarrhea. On the other hand, it can cause some constipation. The more common side effects are dizziness and headache, and in a very small proportion of people on Mimantine, they can experience acute confusion or change in mental status. If this happens, this would be an indication for the patient to call the clinician and possibly discontinue the medication. Next slide, please. And this is just the evidence from an older but a good study showing the impact of Mimantine on slowing loss in activities of daily living. So this is a functional scale, the ADCS ADL, and it shows that over a period of 28 weeks, the people on Mimantine fared significantly better in retaining their loss, in retaining their activities of daily living. So this is really important to patients because they may or may not care about one or two points on the MMSE, but they do care about being able to bathe themselves or being able to pick out their own clothes or not being needed to walk to the bathroom. So the impact of the slowing on, slowing the loss in activities of daily living, and especially over a period of 28 weeks, which means a lot to patients and also delays their placement to facilities because the more dependent they are on daily living activities, the faster placement rates tend to be. Next slide, please. And finally, combination therapy. So this is again, sorry, this is a graph showing monotherapy versus placebo or add-on combination therapy versus the monotherapy and placebo. The gray arm is the placebo arm and the blue arm is the treatment arm with the combination therapy. And it shows that at every single endpoint, the combination therapy was far superior to placebo. And it outperformed placebo in cognition, daily functioning, behavior, and global severity. Next slide, please. This is a safety and tolerability for the medications overall. So memantine added to denepazole, placebo added to denepazole, and for both moderate to severe AD versus moderate AD. And the most common side effects were dizziness, a small risk of agitation, and a small risk of diarrhea. Next slide, please. All right. And so this is a 2020 network meta-analysis on the combination therapy. It looked at 54 trials and showed that the combination therapy, the combination of the cholinesterase inhibitor plus memantine was more effective in improving cognition as measured by the ADAS-CoG, global assessment, daily activities, and it also had significant improvement in neuropsychiatric symptoms. Next slide, please. All right. So now we'll talk about anti-amyloid therapies, which are the new and emerging medications in Alzheimer's disease. So as Dr. Gopalakrishnan mentioned, amyloid plaques are a pathologic hallmark of Alzheimer's disease. And in the literature, there's found that a rare mutation that blocks the pathological amyloid cascade can prevent Alzheimer's disease. So based on this theory, by blocking amyloid, can we prevent Alzheimer's disease? And this amyloid blockage is what is the basis of these emerging anti-amyloid therapies. Next slide, please. So the goal is to develop disease-modifying treatment for Alzheimer's disease in addition to the symptomatic treatments, such as cholinesterase inhibitors and memantine, which are the current mainstay of therapy. The primary target are the amyloid and tau proteins. And there are three main anti-amyloid therapies, which have been approved by the FDA. Aducanumab was approved, but is no longer in clinical use in the U.S. Lacanumab received full approval in July 2023. And the newest is Donanumab, which received full FDA approval in July 2024. And Lacanumab and Donanumab have both been shown to slow down the progression of the disease. Next slide, please. So the evidence for Lacanumab comes from Clarity AD, which was an 18-month multicenter, double-blind, placebo-controlled, parallel group trial with over 1,700 participants. The primary endpoint was the CDR sum of boxes. And the results showed that there was a 0.45 point decline on the CDR sum of boxes. This may not seem a big deal, but each point on the CDR sum of boxes essentially signifies a whole stage of dementia. So a half-point reduction is quite significant. And there was a sub-study for the Clarity AD study, which showed greater reductions in brain amyloid burden with Lacanumab than with placebo. And additionally, there was also a 1.44 point decline on the ADAS-CoV-14, so indicating further cognitive improvement. And two points on the ADCS ADL-MCI. So this is the activities of daily living scale, which measures daily functioning as opposed to cognitive functioning, which is measured by the ADAS-CoV. Next slide, please. So these are the results from the Clarity AD study. On the graph to the left, you can see the comparison of placebo versus Lacanumab on the CDR sum of boxes score. So this is the clinician dementia rating scale that measures the clinical progression over time. And the results, so you can start to see that Lacanumab separates from placebo at approximately the six-week mark. And then at 18, sorry, this is months, not weeks, at the six-month mark. And then at the 18-month mark, Lacanumab was significantly superior to placebo in the CDR sum of boxes. On the graph to the right, we can see the amyloid burden on PET as measured as on placebo versus Lacanumab. And in this case, less is more. So with the placebo, with the individuals on placebo, their amyloid burden on PET did not change over time. It slightly increased, but it definitely did not decrease. On the individuals on Lacanumab, their amyloid burden on PET starts to decrease and then continues to decrease progressively for the first 18 months. And then at the 18-month mark, it's decreased by over 50 centiloids, which is quite significant. Next slide, please. This is a similar data from the results of the clinical trial that led to the approval of Donanumab, which was the most recent anti-amyloid therapy to be approved. So Donanumab was associated with decreased amyloid burden and 35% slower cognitive decline compared to placebo. Again, on the slide to the left, you can see the clinical functioning as measured by the integrated Alzheimer's disease weighting scale on Donanumab versus placebo. And while individuals on placebo continued to worsen, people on Donanumab had significantly less worsening. And a similar graph on the right showing the change in amyloid PET over time. So the individuals on placebo did not have any change in amyloid PET. They did not have any decline in amyloid PET. However, the individuals on Donanumab, similar to the individuals on Leucanumab, started to have a reduction in the amyloid PET. And then at the 76-week mark, there was a reduction of almost 70 centiloids. Next slide, please. So these medications sound almost too good to be true when we look at the amyloid centiloid data, but they come with their own side effects as well. So, well, let's focus on the Leucanumab and Donanumab, which are the current medications under approval. And there was a slightly increased risk of headache and falls compared to placebo and a significantly increased risk of infusion related reactions, particularly with Leucanumab. Next slide, please. But this is the side effect that we really worry about, aria or amyloid related imaging abnormality. In the process of removing amyloid from the brain, Leucanumab and Donanumab and other mabs have a risk of causing microhemorrhages or microedemas in the brain. The probability of the side effect correlates with number one, the potency of the drug. So the higher the dose, the higher the risk. And number two, the presence of the APOE gene. Since they are imaging abnormalities, a lot of times they can only be seen on neuroimaging or on MRI. The majority of arias are asymptomatic, and so routine MRIs are rented into the treatment protocol to be able to identify any emerging asymptomatic arias and be able to either intervene or modify the treatment protocol accordingly. Next slide, please. So aria can be two kinds, either aria H, which is intracerebral hemorrhage, or aria E, or vasogenic edema. And like I said, the majority of aria is asymptomatic, so people don't know that they're having an aria. Approximately 5% of those on anti-amyloid therapies will develop symptomatic aria. Symptoms can be nonspecific, but generally headache, flu-like symptoms, vision changes, acute mental status change. Homozygotes for APOE4 gene have the highest risk of aria, and so genetic testing for APOE4 and counseling about the elevated risk of aria is important prior to starting treatment. And because the majority are asymptomatic, brain MRIs are used to monitor for aria consistently during the treatment. And then the management of ARIA is determined by the presence of symptoms and the severity of the image changes. So, next slide please. So this is just a table that shows the incidence of ARIA in Dunanimab and Leucanimab from the Trailblazer and the Clarity AD trials, which were the trials that led to their approval. The incidence of all ARIA in Dunanimab was close to 40% and Leucanimab was close to 30% as compared to around 9% for placebo. And the risk of symptomatic ARIA was significantly lower, 6% for Dunanimab and about 3% for Leucanimab. And the discontinuation rate for Dunanimab was only about 15%. And for Leucanimab was about 7% as compared to 3% for placebo. And finally, the risk of death was under 1% for both Leucanimab and Dunanimab. So this highlights that while ARIA is an important side effect to counsel patients on, to monitor for, and to appropriately identify and intervene if it does occur, the majority of people who do have ARIA will be asymptomatic and the risk of death with these treatments is actually fairly low. Next slide please. So the key takeaways for pharmacological management, that newly diagnosed patients with mild AD should be treated with cholinesterase inhibitors. As with all geriatric adults, start low and go slow. Combination therapy of cholinesterase inhibitor and memantine can be used in either newly diagnosed patients with moderate AD or people who progress from mild to moderate AD. Newly diagnosed patients with severe AD should be treated initially with memantine and cholinesterase inhibitors can then be added. In mild AD, memantine monotherapy may be used when a cholinesterase inhibitor is not tolerated. And a combination with a cholinesterase inhibitor should be used when the disease is progressing more rapidly than expected. For patients who have advanced to profound disease, which means they have either lost all cognitive and functional abilities, they've lost all their ADLs, they're in hospice, they're in, you know, placement, at that point the treatment may be discontinued. However, for those individuals who are in mild or moderate stages, and they're hospitalized for an acute illness or medical hospitalization, the AD therapy should be continued during that time. The emerging disease modifying therapies that now exist for AD include lacanamab and danatamab, and these are only approved for mild AD and MCI due to AD. And so early detection and referral of AD is vital for consideration of anti-amyloid therapies, because they are not approved for use in moderate and later stages. And finally, ARIA is a potential side effect of anti-amyloid therapies, and thus counseling patients and monitoring with MRI during the course of treatment is important. And with that, we'll move on to questions. Thank you. Thank you very much, Dr. Gopalakrishnan-Joshi for that wonderful presentation. And, you know, now we will open up for questions, so I'm going to start reading the questions as they come in. The first question we have, I practice in a rural area, and there are few options for neuropsychological referrals. In terms of workup for AD, when should I be thinking about referring to a specialist? I feel pretty comfortable with ordering basic labs and an MRI. CSF would be more challenging to do. PJ, do you want to take it or do you want me to go ahead? I'll go ahead and start. So, if somebody meets clinical criteria for Alzheimer's disease, that they have progressive cognitive deficits, significantly different than their baseline, that are starting to affect their functioning, preponderance of memory complaints, and older in age, if they meet the clinical diagnosis of AD, then you've made the diagnosis. You don't need to make a neuropsych referral. Neuropsych referral is handy when the presentation is atypical. So atypical would be very young in age, under age 50, predominance of psychiatric symptoms over cognitive symptoms or predominance of neuropsychiatric symptoms over cognitive symptoms, trying to differentiate between AD and FTD and DLB, multiple symptoms coexist. So if you've made the clinical diagnosis of Alzheimer's disease, you've done the rule-out labs of ensuring that this is not due to reversible dementia like hypothyroidism or B12 or folate, and you've done a brain MRI to rule out structural changes, you've made the diagnosis. You can go ahead and you can start cholinesterase inhibitors and you can give the patient the diagnosis. You don't need to make a neuropsych referral for those types of cases. Thank you, PJ, for that wonderful answer. Now the next question, any guidelines in the role of functional medicine or functional psychiatry in a workup and management? I don't know that. PJ, do you have any thoughts? So Ganesh, do you want me to chip in? Please, yes. My assessment of the situation, given what Dr. Joshi just now said, you know, when you do a workup for reversible causes, you know, and as Dr. Gopalakrishnan pointed out, there are the non-modifiable risk factors, you know, age, sex, family history, you can do nothing about. But all the other modifiable risk factors can be done with good medical history, good rollouts, appropriate lab work, which do not necessarily need to include, you know, neuroimaging or LP or any of those. We're hoping that the biomarkers will come in. So majority of the cases, you know, the role for functional medicine or functional psychiatry is not there. But you do get time to time complicated cases where you're not exactly able to tell if it's really because of, you know, a dementia that is happening or is it because of, you know, a reversible type of dementia because of either infection or due to, you know, depression or due to other conditions. So in situations where there is more psychological issues, where neuropsychological testing you've already done, and it shows some impairments, those times are where I think functional medicine would actually come in. That's my take, having, you know, referred one patient for functional medicine in my 20 plus years career as a geriatric psychiatrist. Do you guys agree on that? Yeah, you know, there's a lot of different approaches and people will come in and ask for different types of testing. Right now, I think the evidence supports what we just outlined where basic laboratory testing, MRI, there's definitely, you know, a place for us to counsel patients about like healthy living. I mean, this, you know, 40% of the attribution comes from lifestyle factors. And as we spend a lot of time talking about physical exercise, even if they have mild cognitive impairment or even mild stage of dementia, we would talk about improving their physical exercise and cognitive stimulation and having a healthy diet. So those things should be part of our management plan. So, but workup wise, I think sticking with the basics is adequate to treat majority of the patients. Any additional questions for our expert panel? If not, I'll put a question which, you know, we were talking about before we started the webinar. You know, this whole diagnostic criteria that Clifford Jackson and their colleagues have done, and that is an updated version from the International Working Group as well. Once you have your biomarker positive, that means you have the illness, right? So how important is it, how you frame that particular information for patients? Because to me, if you tell somebody that they have an Alzheimer's disease, they're really asymptomatic, it becomes highly problematic because you probably are putting them on a, like a death sentence for two decades, three decades, right? They're going to be living in fear. So your thoughts on how you would, you know, counsel on when you get the blood biomarkers? And second question on, you know, the diagnosis after that. Yeah, I think that's a really important thing for us to bear in mind. And I think that's one of the reasons why this workgroup was very specific in putting that in the recommendation not to test or diagnose patients who are asymptomatic at this point. Because I think one thing is to diagnose them and then say, we can't do anything about it. We just have this information. So if there is a prevention therapy, which there's plenty of clinical trials going on right now where we're testing out like Anamab, Donanamab, and other medications in the prevention space, we are identifying people who have elevated amyloid levels and getting them even before they're symptomatic and seeing if this makes a difference in preventing Alzheimer's disease. If we have a preventive medicine, if we have a preventive therapy, then there is definitely a scope for identifying these patients with biomarkers and having that counseling. But otherwise, I agree with you, it's a very big psychological burden to bear. And I think we really have to resist the urge to comply with some of these patients' requests. Sometimes they come in and say, my mom had Alzheimer's disease. I want to know if I have the disease. And we can jump in and order a test, but without understanding or completely discussing with each of these patients the implications of knowing that information. Psychologically, it also brings in other questions like insurance coverage. Like, does that risk increase? Like, will that affect their coverage decisions? Those type of questions come into play too. So really a very extensive counseling should be conducted before and after the testing if you do go with it. So the next question is, how do you decide whether a patient with MCI gets a Dananamab or Lacanamab? So in my clinical practice, mostly it's related to what is available right now. So we have been able to operationalize Lacanamab over six to seven months. It just took a lot of time for us to make sure the system was ready to take on this new treatment. So we just have Lacanamab. I think we are anticipating Dananamab to be available early next year, but we don't have that clinically available. But I think once it is available, it is going to be a discussion with the patients about the pros and cons of each of these treatments. I think Lacanamab has some advantages that they have a lower ARIA risk right now. But Dananamab did present some findings at CTAD this year where a small tweak in their dosing regimen or the titration regimen reduces the ARIA risk quite a bit. So I think that will put in the same playing field as Lacanamab. But Dananamab has the once a month infusion advantage. And also they have an opening where after 18 months, 12 or 18 months based on the patient, if we see that the person is amyloid negative or we have cleared out most amyloid, they could discontinue the medication. So that's an option with Dananamab compared to Lacanamab, which is right now supposed to be ongoing. Thank you. Thank you for that. So the next question is, can you elaborate on what specific blood tests exist for the diagnosis of Alzheimer's disease, including sensitivity and specificity? PJ, do you want to go? I've been speaking too much. Why don't you go ahead and take this one and we'll take the next one. So I think the most sensitive thing, if I have to hedge my bets on one thing, that's going to be the Ptau 217. Sorry, 231 is going to be another big indicator too. But right now, everything indicates the Ptau 217 is going to be the biggest biomarker we are going to use. As I mentioned, the amyloid biomarkers have some challenges being used in the blood. And that's where the Ptau becomes really important. It can be a standalone test and we can get into like high 90s in specificity and sensitivity to identify patients with Alzheimer's disease. And it has high correlation with the CSF amyloid levels, PET amyloid and Ptau level. Sorry, PET amyloid. It's more correlated with the amyloid pathology. So that's where I think is the biggest advancement. Next question is, are there, are any of these medications sufficient to treat neuropsychiatric symptoms of Alzheimer's disease? For example, patients with mild to moderate Alzheimer's disease and hallucinations? So I'll talk about cholinesterase inhibitors and memantine first because we have a lot more evidence on them. So cholinesterase inhibitors and memantine can be helpful for milder neuropsychiatric symptoms like anxiety, low frustration tolerance, some mood changes. But it's not going to be sufficient for acute psychosis. So it's part of the treatment algorithm of the behavioral and psychological symptoms of dementia because not only do the cholinesterase inhibitors and memantine help with cognition and ADLs, they have also shown to improve some of these milder neuropsychiatric symptoms. However, when symptoms progress to either the level of frank psychosis, acute psychosis, severe aggression, then these medications might not be adequate and then either atypical antipsychotics might need to be added. There is an entire presentation on the APA Learning Center on the management of behavioral and psychological symptoms of dementia. So if you're interested, you can take a look at that in a much more in-depth manner. As for licanumab and dananumab, there is no evidence yet. The clinical trials did not look at neuropsychiatric symptoms as one of the outcome measures, and it hasn't been in clinical practice long enough for us to establish anecdotal evidence of its impact on neuropsychiatric symptoms. Thank you very much. So the next question is, any clinical pearls in regards to alcohol-related cognitive impairment and management beyond sobriety? What would be different in neuropsychotic testing profile? I think this is a very controversial field for dementia space. I think most people will say that there is like a J-shaped curve between alcohol use and dementia risk itself. But once you have cessation, which is what we would recommend for heavy alcohol use, the question is, is this contributing significantly to the diagnosis? As you saw earlier in the slide, excessive alcohol use itself can be a risk factor for Alzheimer's. So someone presenting with cognitive issues, even after they have stopped excessive or even alcohol use, they could still have an Alzheimer's disease process going on because it might have initiated already. Or they may have static deficits going on from excessive alcohol use and the damage that is already caused by it. So I think monitoring is going to be very important to see if these things progress over time. You could still use the same biomarkers and say this person is at risk or do they already have the diagnosis and prognosticate at that level too. But cessation is going to be the most important thing. I don't know if I missed any other part of the question. No, that's it. What would be the difference in neuropsychological testing profiles? It won't be very different. I think the typical pattern for Alzheimer's disease is an amnestic presentation, rapid forgetting, difficulty in memory and learning. And that may still pan out with patients with excessive alcohol use. But people with some vascular disease or even deficits from longstanding alcohol use, it may be affecting more their attention and executive functioning. So that might be some difference. But those are domains that get affected even in Alzheimer's disease. So it's hard to differentiate just on a neuropsych testing. Thank you. So the next question is a patient of mine with MCI is interested in combination therapy. Are there contraindications or downside to this? Yeah, so I think the first thing would be to establish if the MCI is due to Alzheimer's disease. If the MCI is, you know, thought to be not due to Alzheimer's disease, either the pattern, either the cognitive presentation is not clearly amnestic or it's fluctuating. Or there are other neurological or established neurological or psychiatric conditions that may be contributing to the MCI. Then the combination therapy will not be that helpful. If the MCI is secondary to Alzheimer's disease, then I think the most important thing is to counsel the patient. So certainly in clinical practice, I have seen patients with MCI due to AD on combination therapy. It is done. I think the most important thing is to counsel the patient on the fact that number one, it is off label. Number two, it is not going to reverse or halt progression. It will only slow down the progression. But progression from the MCI to the AD stage is still inevitable. And third, counseling them on the potential side effects. So the side effects are still present in the MCI stage. So for cholinesterase inhibitors, the GI side effects, risk of bradycardia, hypertension, and for memantine, the headache, dizziness, potential mental status changes. Thank you, PJ. So the next question is, when do you give MCI patients the amyloid-lowering drugs? I think it's a process of discussion with the patient. So once we diagnose patients with MCI, the next stage, and that's a lot of times it's clinical. And then in our clinical practice, we would say, let's go ahead and do an amyloid PET scan to make sure, or they can do a CSF analysis too for amyloid and APOE testing. So once we have both those information and they have elevated amyloid in the brain, we go with their risk specifically based on the APOE for testing and say, you know, these are the pros and cons. And you can start patients on leucanumab once you have made sure that they are not on anticoagulants. There are a bunch of exclusion criteria. There is an appropriate use recommendations paper that a lot of people follow. So it kind of provides guidelines as to what exclusions you should incorporate. And if they don't meet any of those things, you can get people started on leucanumab. Thank you for that answer. I think we have answered all the questions. Thank you both for your expertise and for your time. So I just wanted to say that thank you all for our audience for joining. Be sure to claim your APA credits from the APA Learning Center. Please be sure to join our next webinar on Advances in Obesity Treatment, Medication Management for Psychiatrists by Dr. Vikas Gupta, who is the founder and CEP of Holistic Wellness. This webinar will be held on Wednesday, December 4th from noon to 1.30 p.m. Eastern Time. So be sure to register soon. Thank you all and have a wonderful day and happy holidays to everyone. Bye-bye.

Alzheimer's disease

diagnosis

therapeutics

Dr. Ganesh Gopalakrishna

Dr. Pallavi Joshi

cognitive impairment

amyloid proteins

tau proteins

cholinesterase inhibitors

memantine

Lecanemab

Donanemab

biomarkers