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Alzheimer's Disease: Insights Into Optimal Care

  • Authors: Ronald C. Petersen, MD, PhD; James E. Galvin, MD, MPH; Gregory A. Jicha, MD, PhD
  • CME / CE Released: 10/11/2022
  • Valid for credit through: 10/11/2023
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  • Credits Available

    Physicians - maximum of 0.75 AMA PRA Category 1 Credit(s)™

    Nurses - 0.75 ANCC Contact Hour(s) (0.25 contact hours are in the area of pharmacology)

    You Are Eligible For

    • Letter of Completion

Target Audience and Goal Statement

This activity is intended for neurologists, nurse practitioners (NPs), and nurses involved in the care of patients with Alzheimer's disease (AD).

The goal of this activity is that learners will be better able to diagnose early forms of AD and understand investigational therapies for AD management.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinically relevant tools to assess cognitive impairment in older adults 
    • Mechanism of action of emerging pharmacotherapies for the management of AD 
    • Clinical trial data for emerging pharmacotherapies for the management of AD
  • Have greater competence related to
    • Accurately diagnosing early stages of AD 


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Session Chair

  • Ronald C. Petersen, MD, PhD

    Professor of Neurology
    Cora Kanow Professor of Alzheimer's Disease Research
    Director, Mayo Alzheimer's Disease Research Center
    Mayo Clinic College of Medicine
    Rochester, Minnesota


    Ronald C. Petersen, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Biogen, Inc.; Eisai, Inc.; Genentech, Inc.; Nestle, Inc.; Merck, Inc.; Roche, Inc.


  • James E. Galvin, MD, MPH

    Professor of Neurology
    Director of the Comprehensive Program for Brain Health
    University of Miami
    Miller School of Medicine
    Miami, Florida


    James E. Galvin, MD, MPH, has the following relevant financial relationships:
    Consultant or advisor for: Alpha Cognition; Biogen; Cognivue; Eisai; PassageBio

  • Gregory A. Jicha, MD, PhD

    Professor of Neurology
    University of Kentucky
    College of Medicine
    Lexington, Kentucky


    Gregory A. Jicha, MD, PhD, has the following relevant financial relationships:
    Contracted researcher for: AbbVie; Alector; Biohaven; Eisai; Lilly; Neurovision; Novo Nordisk


  • Meg Monday

    Senior Director, Content Development, Medscape, LLC 


    Meg Monday has no relevant financial relationships. 

  • Frances McFarland, PhD, MA

    Associate Medical Education Director, Medscape, LLC  


    Frances McFarland, PhD, MA, has no relevant financial relationships.   

Compliance Reviewer/Nurse Planner

  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC 


    Lisa Simani, APRN, MS, ACNP, has no relevant financial relationships. 

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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    For Nurses

  • Awarded 0.75 contact hour(s) of nursing continuing professional development for RNs and APNs; 0.25 contact hours are in the area of pharmacology.

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Alzheimer's Disease: Insights Into Optimal Care


How Low Can We Go?: Striving for Early Diagnosis of Alzheimer's Disease



Hi, I'm Dr. Greg Jicha from the University of Kentucky, here to speak on Alzheimer's disease. Specifically today, we're going to discuss how low can we go striving for an early diagnosis of Alzheimer's disease. We all know that the concept of Alzheimer's disease has been an evolution. It's been an evolution ever since Alzheimer first described it, but really picking up pace in 1984, with the NINCDS-ADRDA criteria and the establishment of the NIA ADRCs, an entire network set up to really move the field forward. This was the first real formal criteria that was put together, agreed upon from a multicenter standpoint. In the same year, beta amyloid discovered as a key component of the Alzheimer plaque. Moving forward a few years, the consortium to establish a registry for AD expanded that initiative on an international stage. And in the same year, tau discovered as the key protein in neurofibrillary tangles. Shortly thereafter, mutations, leading to autosomal dominant AD and risk genes like APOE4 were identified. And by the end of the century in 1998, CSF assays had already been developed to measure ABeta and tau in spinal fluid to provide biological confirmation of diagnosis. It was about the same time in 1999, that an emerging concept in the field became popularized. This was the concept of mild cognitive impairment led by Dr. Ron Peterson in the Mayo group. Shortly thereafter, we developed the ability to begin to image amyloid plaques in the brain with PET scans. This led in 2011 to the development of the NIA-AA criteria for Alzheimer's disease dementia. And then in the theme of how low can we go pushing back to MCI of the Alzheimer type and even further for research purposes, the concept of preclinical AD, and this has been updated in 2018 with a research framework that is paving the way towards earlier and earlier diagnoses to be brought into clinical care over time. So let's go back and really talk about that concept of mild cognitive impairment. Everyone realized that with a process like Alzheimer's, this is occurring over decades, and one doesn't move from normal to dementia overnight. And so there must be an intervening stage. And so this is the stage that was referred to and still is referred to as mild cognitive impairment. Prior to overt functional impairment, a stage where early cognitive decline is becoming evident, but they're still able to compensate. And we know that one of the key forces for moving the concept of mild cognitive impairment forward was that it identified folks at risk for decline over time. As you can see in the lower left hand corner of the screen, a Kaplan-Meier survival curve, showing that 80% plus patients with MCI will convert to dementia over an eight year period. And really building on that we know that it's not three steps, it's not normal, MCI, or dementia, but that this is a slope. And so even in the normal stage, we might start to see early signs of decline that tells us that we're on this slope moving towards fulminant dementia. So MCI needed to be operationalized. How would we put this into play? And so this schema was developed by the Second International Working Group on MCI. Does the subject have a cognitive complaint? Are they not normal for age, but not demented? No functional decline. And do we have objective evidence for cognitive decline? And if so, they met criteria for MCI. Then the question had to be asked, is the memory impaired, or is it some other cognitive domain? And this separates us into amnestic and non-amnestic MCI, and then asking the question further, is it just one domain or are there multiple domains involved? And the purpose of this to really break this down and give us four different types of MCI was really to begin to set up a framework where we might be able to predict the underlying etiology, a single domain amnestic may represent early Alzheimer's disease as other domains come on board, perhaps moving a little bit further down that path towards ultimately functional impairment and Alzheimer's disease. And with these discoveries and movements in the field towards MCI, really the feel needed new tools, more sensitive tools to detect, not just fulminant dementia, but new tools for MCI. So the AD8 brief set of eight questions has very good sensitivity and specificity [05:33 – please restore] for detecting Alzheimer's or [05:42 – remove cough] for detecting mild cognitive impairment with a simple bedside question and answer session. The Montreal Cognitive Assessment began to provide more sensitivity for the detection of early diagnosis of mild cognitive impairment, improved over the MMSE, which was the prior chosen test in the field. Again, getting better and better at detecting earlier and earlier diagnoses. With the concept of MCI, we were faced with a challenge as a field. Were we ready for this? And that is a question that has been answered in the literature. And this is a study that I did years ago, looking at folks that received a diagnosis of mild cognitive impairment, not folks that were coming into my memory disorders clinic, but people that we were seeing in the community who thought they were normal, but we were detecting decline. And we were shocked actually, that almost a third of patients. Well over a quarter, when you give an unsuspecting person a diagnosis, of MCI, it is not always welcome. And many people will refuse work-up. So as we push back to earlier and earlier diagnosis, we do have to keep this in mind. Is the population, are our patients ready for us to go earlier and earlier? Very, very important. Simultaneous with the clinical development was a lot of development in the field of neuropathology. So early studies looking at the pathology of MCI showed that it was an intermediate state between the pathology seen in controls and that seen in Alzheimer's disease, but also notably that it was not all Alzheimer's disease. There indeed is mixed pathology and other neuropathologic causes for a diagnosis of MCI. And that's really come to a head as the field has begun to embrace the concept of mixed dementia that even in MCI, a large number of cases, 60% representing mixed disease, not just pure Alzheimer's disease. So while we used to think, well, we make the diagnosis of MCI and then we choose an underlying etiology, and you could only pick one. Now we know that the field is overlapping what's happening in the brain is actually a confluence often of multiple comorbid pathologies. But neuropath discoveries pushed even further with several studies, key studies in the field, looking at the neuropathology in normal human brains, people who are cognitively normal. And what we find is that there are plaques and tangles that can be seen in humans. And as far back as 1992, the concept of preclinical AD was born. And this has been pushed forward by repeated analyses of normal pathology; the pathology in cognitively normal individuals. And now we know if we look at the graph on the left, that in green, the prevalence of plaque seen at autopsy in human controls starts to rise after about age 45 and exponentially increases. And if we look at the prevalence of clinical AD in red, that lags about 15 years behind, and now of course, with the advent of PET amyloid, PET imaging, we are able to actually detect in living human beings, this buildup of amyloid plaques, again, 15 years on average, before the development of cognitive and functional decline sufficient to meet Alzheimer's disease. So indeed preclinical Alzheimer's disease is at the forefront of how low can we go. Other antemortem biomarkers have been developed as well. Many of these still in research phases, Tau PET now gives us the ability to look at the earliest stages of neurofibrillary tangle formation, FDG PET allows us to see the metabolic consequences of an Alzheimer type process, and then even looking at comorbid pathologies with DAT scans, dopamine transporters SPECT scans that can pick out or identify folks with contributing Parkinsonism or Lewy body disease. And of course, CSF AD biomarkers really still at the forefront detecting the majority of clinically diagnosed AD cases, the majority of MCI cases, although not all and up to a third of cognitively normal individuals. All of this work in biomarkers has allowed a biological model for AD progression to be developed, which actually begins 10 to 20 years before one would meet criteria for Alzheimer's disease in the presymptomatic or preclinical phase with amyloid rising neurofibrillary tangles, building up brain metabolism and neuronal dysfunction followed by death atrophy, and eventually cognitive decline in functional impairment. So understanding the disease course really opens the field to think about how low can we go. Amyloid PET of course, gives us the ability to look at folks that are in that preclinical stage. And what we know from studying families with autosomal dominant Alzheimer's disease is that 10 years before their earliest signs of cognitive decline, we're already seeing changes on those PET scans. And we also know that AOE risk genotyping can predict who might be building up amyloid while people are still cognitively normal in a gene dose dependent manner. The more E4 genes you have, the more likely you are to be building up this amyloid while you are cognitively normal. So the question is, is preclinical AD really preclinical or are there subtle cognitive changes that we might be able to pick up on? And this is a study that was done with neuropathologically confirmed preclinical Alzheimer's disease, where we are able to see that super span, wordless, constructional, Praxis, composite, cognitive measures, and animal naming can all be seen to be subtly declining long before the diagnosis of modeled cognitive impairment, let alone Alzheimer's disease. So now we have a framework where we've moved from just diagnosing Alzheimer's in the dementia phase with amyloid tangles, cognitive decline, and functional impairment to identifying and diagnosing it in a prodromal phase, the phase of MCI with amyloid neurofibrillary tangles, and mild cognitive changes, but no functional impairment, all the way back to preclinical disease with early amyloid abnormalities and no other clinically evident impact of the disease at that point. And now pushing back even further we’re in the era of blood based biomarkers and development. And these blood based biomarkers will make it very, very simple to push back that diagnosis earlier and earlier. They show good association with amyloid PET, with tau PET, with CSF, there is still some variability and technologically working this out still requires some development, but these biomarkers are already moving into practice. So this is just one example, with an area under the curve of 0.9, which is fantastic using a combination of plasma biomarkers, APOE4 status and age to come up with an accurate blood based test for Alzheimer's disease. One of the things that the blood biomarkers have shown us is that many people can be positive in these blood biomarkers long before there's CSF and/or their amyloid PET turns positive. And so the thought was, are these just false positives and they really don't have the disease, but work done by Suzanne Schindler at Washington university in St. Louis has shown that if you follow these folks with elevated plasma biomarkers over time, they all convert. And so we've set up a scenario where the blood biomarkers may change first, followed by CSF, eventually followed by the amyloid entangle accumulation that is measured via PET scanning. So what are the implications of where we're going? Well, we are going to be able to more easily diagnose patients without the burden of a history or labor intensive workup, cognitive testing, expensive PET scans. On the downside, we may falsely diagnose patients. And what do we do about giving somebody a diagnosis of pre-clinical Alzheimer's disease when they're still normal? And so both a blessing and a curse, being able to push back, how low can we go to the pre-clinical stages 10 to 20 years before a memory problem occurs. And we really need other biomarkers because it's not just about plaques and tangles. We know that we have TDP43 pathologies seen in late and alpha synuclein in Lewy body disease and vascular changes. And as we build this armament, the accuracy of our antemortem diagnoses, even pushing back to earlier stages of disease is going to become more and more accurate. So we'll ask that question again. Are we ready to begin diagnosing preclinical ad in a clinical setting? And this is work that's come from Jeff Burns at the university of Kansas, looking at people's response to having their diagnosis of preclinical Alzheimer's disclosed again, people cognitively normal, no functional impairment being told, yes, you have early amyloid buildup in your brain, and this is placing you at risk to eventually develop full blown Alzheimer's disease. And it turns out that anxiety was not significantly elevated. Neither was depression after being told. So our patients may be ready for this. They may be ready for us to take them back even further, and we can go back further. We can look at risk factors for Alzheimer's disease. And this is something that came out of Lancet in 2020, looking at the life course of Alzheimer's disease with impacts at birth from genetics in early life, via lower education, midlife with hearing loss, TBI, hypertension, alcohol overuse, and obesity, and in late life as well. So the question may not be how low can we go? The question may be, how low should we go? And given all that we've discovered we can really look at this. How low can we go? Well, we can go back to birth for those with high genetic risk, autosomal dominant Alzheimer's disease. Maybe we should not go back that far. Maybe we should go to midlife where we can intervene on those modifiable risk factors, or should we continue to wait until the clinical signs and symptoms of mild cognitive impairment and or dementia appear? I think if there's one thing we've learned from the field of cancer earlier, intervention is always more effective. So again, not how low can we go? How low should we go? I'd like to thank you for your attendance and interest in this topic today.

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