Current Understanding of Alzheimer’s Disease Pathology

Four Alzheimer’s disease expert discuss our current understanding of Alzheimer’s disease pathology and the presence of amyloid and tau pathologies in patients.

Marwan Sabbagh, MD: Hello, and welcome to this Neurology Live® Peer Exchange titled “Expert Perspectives on Recent Advances in Alzheimer’s Disease.” I’m Dr Marwan Sabbagh, a behavioral neurologist and a professor of neurology in the Alzheimer and memory disorders division in the department of neurology at the Barrow Neurological Institute in Phoenix, Arizona. Joining me in this discussion are 3 of my colleagues. To my right is Dr Alireza Atri, a cognitive neurologist and the director of Banner Sun Health Research Institute in Sun City, Arizona. Also joining me is Dr Sharon Cohen, a behavioral neurologist at the Toronto Memory Program in Toronto [Ontario] Canada. Finally, also joining me is Dr Eric McDade, who is a professor of neurology at the Washington University School of Medicine in St. Louis, Missouri.

We’re going to discuss recent advances in Alzheimer disease. We’ll share updates on the use of blood and CSF [cerebrospinal fluid] biomarkers and imaging modalities in diagnosis and treatment of Alzheimer disease. We’ll discuss data from emerging Alzheimer therapies that were presented at the CTAD [Clinical Trials on Alzheimer’s Disease] 2022 meeting, and the promise these therapies represent for the future of Alzheimer care going forward. Let’s get started.

Our first topic is pathophysiology and diagnostic updates in Alzheimer disease. Dr McDade, I’m going to pose this question to you. What is our understanding of causes and pathophysiology of Alzheimer disease? Please comment on recent reports that cast doubt on the amyloid hypothesis, as well as the role of beta-amyloid deposits in the progression of Alzheimer disease.

Eric McDade, DO: Thank you, Dr Sabbagh. Our understanding of Alzheimer disease continues to evolve with the science. You mentioned amyloid. One of the important things to consider with Alzheimer disease is the role that amyloid has played. Diagnostically, it’s required to make the diagnosis of Alzheimer disease. One of the complexities of Alzheimer disease has been the recognition, for 40 to 50 years, that you can have amyloid pathology in your brain at the time of death and not have symptoms.

Part of the issue with understanding the disease has been this contradiction that the same pathology that’s associated with the disease, amyloid, can be associated with no symptoms. However, we do understand increasingly, and what’s led the field over the last 20 to 30 years, is that amyloid plays a fundamental role in leading to the onset and the development of Alzheimer disease. We know that amyloid pathology develops up to 20 years before symptoms have developed. The development of technologies has allowed us to understand that because we can see the pathology in people as they’re living now in a cognitively normal state.

But what we know about the symptoms, and what’s led to controversy with regard to the role that amyloid plays, is that when we look at the actual symptoms of Alzheimer disease, they’re much more tightly linked to the tau pathology, particularly those neurofibrillary tangles that we see within the cells. Also, things like synaptic loss are associated with this evidence of excess inflammation in the brain, which is a normal response to having amyloid pathology in the brain. What’s been challenging about this is linking this disease, which develops over 20 years or longer, to differences of when those pathologies develop and how we can subsequently address those. What we now know from information that came out at CTAD, as well as information that’s been coming out over the past few years, is that there’s clearly a role for amyloid pathology even at the symptomatic stage of disease. But that probably has limits to how much it affects individuals when they already have symptoms. If we can lower amyloid significantly, there’s an effect. However, knowing what we know about the disease, we know that there are going to have to be therapies that address these other components of the disorder.

Marwan Sabbagh, MD: You bring up the multiple mechanisms. I’ve been hearing some comments recently about coalescing usually around the ATN [amyloid, tau, neurodegeneration] criteria, but that the neurodegenerative diseases are ultimately proteinopathies, and Alzheimer disease is an amyloidopathy. When you talk about mechanisms for the pathology, the different aspects of the pathology, how do you look at this in terms of the proteinopathy approach?

Eric McDade, DO: Proteinopathy allows us to look at this at a higher level. For many years, as all of us were trained, and going back over the last century, we’ve recognized these disorders mostly on their symptoms. When we look at Alzheimer disease, we’ve recognized that it’s typically a disorder of older adults that starts with significant memory problems. When we think about Parkinson disease, another proteinopathy associated with alpha-synuclein protein, we recognize it as primarily a movement disorder that evolves over many years and eventually develops dementia in a lot of individuals, along with other disorders like frontotemporal dementia.

Proteinopathy is the fundamental component that leads to these diseases. But it’s the expression still that we use traditionally to make the diagnosis. That’s changing as we have ways of measuring these proteins in individuals. We can be more precise: this individual, with this core set of symptoms and abnormal biomarkers associated with these protein s, is suffering from Alzheimer, which is alterations in that amyloid pathology and proteinopathy as well as the specific tauopathy. Another individual may develop a Parkinson-like syndrome but have the absence of Alzheimer pathology based on these tests that we use. We can definitively say that this is a Parkinson-associated disorder. We use these to classify the disease more precisely when we think about it. Also, because we can measure those, we can be more specific with how we target them with therapies and know if our therapies are at least hitting that target, and then make assumptions on how that’s related to improvement in the symptoms.

Transcript edited for clarity

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