Epidemiology and Pathophysiology of Alzheimer Disease

Alireza Atri, MD, PhD: Hello, and thank you for joining this HCPLive® Geriatrics Peer Exchange titled “Early Diagnosis, Testing, and Treatment of Dementia.”

Alzheimer disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually, the ability to carry out the simplest tasks. Symptoms of Alzheimer disease, for most people, first appear in their mid-60s. There is currently no cure for Alzheimer disease. However, timely detection, accurate diagnosis, and appropriate management can produce meaningful results for patients and families, and there are drugs in the clinical development pipeline that may be promising.

In this HCPLive® Peer Exchange® discussion, I am joined by a panel of my colleagues, all experts in the fields of internal medicine, geriatrics, geriatric psychiatry, neurology, and neuropsychology. Together, we’ll review the latest clinical trials and provide practical perspectives on approaching, evaluating, and managing the geriatric population affected by Alzheimer disease in your clinical practice.

I am Dr Alireza Atri, director of the Banner Sun Health Research Institute, Banner Health, Sun City, Arizona.

Participating today on our distinguished panel are: Dr Marc Agronin, senior vice president of behavioral health at Miami Jewish Health, in Miami, Florida; Dr Bradford Dickerson, director of the Frontotemporal Disorders Unit at Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts; Dr Mary Norman, medical director at Highland Springs-Erickson Living in Dallas, Texas; and Dr Lynn Shaughnessy, director of neuropsychology at the Cognitive Neurology Unit, Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts.

I’ll pose the first question to you, Marc. The prevalence of dementia due to Alzheimer disease and related disorders is increasing. What are the numbers and projections telling us?

Marc E. Agronin, MD: These statistics are really stunning when you look at them. Worldwide, almost 50 million individuals are living with some form of dementia, and 60% to 70% of these are cases of Alzheimer disease. What’s really concerning is that every year about 10 million new cases are being added. And so, if you project into the next 30 years, this number is going to double and then triple. So we really are facing an epidemic of dementia worldwide, across the board. And obviously with age being the No. 1 risk factor, the number is increasing exponentially. If there’s 1 glimmer of hope here, it is that there have been several studies that have shown some age-specific decreases in the prevalence of Alzheimer disease in the United States and in Europe. This may suggest that some of the healthy lifestyle issues that we’re discovering, that we’ll talk about today, might be having an impact. But the bottom line is that the absolute number is increasing, and we absolutely have to pay close attention to this.

Alireza Atri, MD, PhD: Great. Thank you, Marc. So yes, there are some studies that are showing the incidence rates may be changing because of, potentially, some of the healthy habits, which we’ll talk about a little bit later. But as the number of people in this baby-boomer generation is increasing in the United States, we’re going to have an increased prevalence. Brad, what causes Alzheimer disease?

Bradford C. Dickerson, MD: Well, I think there are a number of theories. Some might be considered competing theories, but I think the prevailing idea is that we have a process that leads to the formation of amyloid plaques and tau-related neurofibrillary tangles that lead to brain dysfunction and, ultimately, neurodegeneration and symptoms. The amyloid hypothesis proposes that there are different pathways that process the amyloid precursor protein that seems to have important functions at the synapse and within neurons in the brain. And 1 pathway is really an unhealthy pathway that can lead to degeneration of portions of the protein that can eventually aggregate. And initially, they may start to form so-called protofibrils that are soluble and still floating around, but may start to interfere with synaptic function. Eventually, they aggregate and become insoluble and form the amyloid plaques that we talk about when we talk about what you see under the microscope in a person with Alzheimer disease.

Somewhere along that process, tau begins to hyperphosphorylate, form tangles within cells, and eventually kill off the cell. It leads to dysfunction, initially, but eventually it kills off the cell and leads to the neurofibrillary tangle that Professor [Alois] Alzheimer also saw under the microscope more than a century ago. So as the tau really starts to take hold in the cells, and it may actually propagate from cell to cell, which is a hot new idea, it begins to lead to network dysfunction within the brain and hypometabolism that you can measure on PET [positron emission tomography] scans that we’ll talk about later. And dysfunction within the network is thought to be one of the real proximate markers of symptomatic onset. So I think the idea is that the network is dysfunctional and then it starts to degenerate. The neurons start to lose their processes that connect them with other neurons and eventually start to die off.

Somewhere in that process, glial cells become active and start to get into the mix possibly as an attempt to clear out some of the pathologic toxic species of these proteins. They may actually contribute to some of the damage in that process, and there’s thinking about neuro-inflammation, as it’s called, and also so-called excitotoxicity, some of the calcium processing that can lead to the degeneration of brain cells. It may be that some of these processes get set off in a way that are not specific to Alzheimer disease pathophysiology, but might be common to other neurodegenerative diseases. And that might be where there are opportunities to develop treatments that could intervene in the process of more than 1 neurodegenerative disease. But ultimately, all of these are a family of diseases that lead to brain cell loss and the pathologies that we can see under the microscope, and ultimately the irreversible degeneration of parts of the brain that control people’s cognition and behavior.

Alireza Atri, MD, PhD: I think this is a very interesting idea about proteins and proteinopathies being causes of neurodegenerative conditions, and that other mechanisms like neuro-inflammation, even vascular dysfunction may be at play. So individuals who are older may have multiple things going on in the brain. Thank you for that, Brad.

Transcript edited for clarity.