A Historical Perspective of Alzheimer Disease

Alireza Atri, MD, PhD: It’s important to have a historic perspective on both the diagnosis and treatment of Alzheimer disease. This is a disease that was thought to be rare back in 1906, when it was described. It was described in a young woman who developed symptoms in her 50s. Back then, the thought was that multiple different conditions caused senility in older individuals, mostly hardening of the arteries, and Alzheimer disease was defined pathologically by amyloid plaques and neurofibrillary tangles that we found out later were components—these proteins, plaques, and the tangles. The thought was that this only affected younger individuals. It wasn’t until the 1970s that there was an appreciation that most people who are older and are showing symptoms have Alzheimer pathology in their brain.

More recently, in the last 5 or 6 years, there’s been a greater appreciation that the hallmarks can start 15, 20, 25 years before symptoms onset. Whereas young individuals may have a very pure form of the disease, older individuals likely have multiple conditions that lead to cognitive impairment and dementia. Alzheimer pathology is one of them, but it’s not the only thing that’s involved. That’s on the diagnostic side. Also, there is an appreciation that it’s not just memory that’s involved. Depending on their vulnerabilities and reserve, individuals can show symptoms in different ways.

For many typical patients, it may be difficulty with new learning and remembering of new facts or life events, but it doesn’t have to be that way. It can be difficulty with executive function, multitasking. It could be visual-spatial abilities, or language, and coming up with the right words. And in many individuals there’s actually a mood component and sleep component that becomes obvious years before people show cognitive symptoms. This could be anxiety, depressive symptoms, or sleep problems. So that’s really the behavioral aspects that have also been appreciated much more.

Ultimately, on the treatment side, we have multifactorial treatments that involve early diagnosis or timely diagnosis, behavioral interventions, medications, both taking away bad medications and adding the approved medications, managing symptoms, managing the environment, having a new language and a care environment that’s conducive to different stages for individuals. And ultimately, having a partnership with the individual and their care partner, and really taking care of the care partner who becomes, in some ways, a patient because their health and their well-being really affects the affected individual’s well-being. So that’s the overview.

Then more recently, because of the advent of biomarkers and seeing the disease process years before onset, there’s been a move toward being able to have a more pathobiological definition that may be disconnected from the symptoms, and coming up with different treatments that can affect amyloid, and tau, and maybe even other things that affect cognition and brain function, including inflammation and vascular brain changes. So it’s an exciting time. Even though we’ve had a number of failures in trials, we’re learning a tremendous amount.

Ronald C. Petersen, MD, PhD: As of spring 2019, we’ve had some disappointing news in the field of the development of drugs for Alzheimer disease. Aducanumab, which was one of the major antibodies against the amyloid protein, was discontinued in 2 major international trials just recently. This was very disappointing to us because we had high hopes for this trial, as it showed that it could remove the amyloid from the brain. But the second question was, did it make any difference clinically? Apparently the studies were stopped for futility because there was not a clinical benefit from the drug.

Nevertheless, that doesn’t mean we’re out of business. It was a major trial, but we’re still moving forward. We think that there are many important therapeutic targets. Among them is amyloid, which still needs to be explored, and there are 50 to 60 compounds under investigation at any given time.