In Alzheimer's Disease, It's Not Always Memory That Goes

Bret Stetka, MD


July 10, 2020

This transcript has been edited for clarity.

Last month, a study was published in Brain Communications defining a subtype of Alzheimer's disease (AD) characterized by impaired executive function —problems with such tasks as organizing and planning. This "progressive dysexecutive syndrome," as it's called, can affect people as early as their 40s and has a much different clinical profile than the memory impairment we tend to associated with the disease. Medscape spoke with Mayo Clinic neurologist and study investigator David Thomas Jones, MD, to explore what clinicians should know about dementia presenting with executive problems.

We usually think of AD as impairing the hippocampus and episodic memory, but we know there are atypical forms. What is unique about the subtype you've described?

Progressive dysexecutive syndrome targets executive cognitive function, which is interesting, counterintuitive, and probably a significant factor in why it's often not recognized and diagnosed in a timely fashion. Some of the keys to identifying these cases are the struggles with, in particular, working memory, multitasking, task completion, and temporal sequencing.

When does it typically present?

Often in people in their 40s and 50s, which is consistent with the hint we've been seeing in the pathologic literature. Melissa Murray and Dennis Dixon, our colleagues at Mayo Clinic in Jacksonville, Florida, collaborated with us, and their pathologic studies have shown that there are particular forms of pathologically defined Alzheimer subtypes in which the hippocampus is relatively spared — and the demographics of those cases certainly include younger ages of onset.

We've known for a while that there's something different going on in younger-onset cases. It's just not clear what clinical phenotypes are associated with them. We've now been able to show detailed analyses in 55 cases of this executive syndrome. It's hard to draw any conclusions or study a disease without a definition. This study provides that definition.

So this subtype had been described in the past, and you and your colleagues have now formally defined it?

Cases with executive-predominant features have been reported in the literature. But we looked at neuropsychological test results of patients with AD and showed that the profile of severe executive dysfunction with relatively preserved memory had occurred in some cases. There just hasn't been a case definition.

These people spend years bouncing around to different providers and struggling at work, losing their jobs, and not knowing why.

One of the initial reports did focus on executive dysfunction, but in a pivotal 1999 paper, Julene Johnson and colleagues coined the term "frontal AD." That's when executive dysfunction began to be tied in with behavior and frontal lobe anatomy. Since that point, we've seen a confusion between the frontal lobe and executive cognition and behavioral problems. And that's where the confusion around the syndrome has centered for 20 years.

What we're showing, along with work from Gil Rabinovici and Rik Ossenkoppele looking at patients with executive dysfunction AD versus behavioral AD, is that these are actually separate syndromes. You should separate behavior and executive function because the frontal lobe may not be involved in many of these cases.

Given that the clinical presentation of dysexecutive AD is so different from the classic presentation, what makes it a form of AD at all? Does PET show amyloid and tau buildup in the brain?

Let's say you had no clinical information on cases, but you're just looking at a brain bank and using current pathologic criteria for grading severity of AD pathology. All these cases meet that.

We saw any combination of three criteria that determine the presence of AD pathophysiology. One was cerebrospinal fluid biomarkers for amyloid and tau; another was amyloid- and tau-positive PET scans; and third was autopsy evidence. Every case had one, if not more, of these criteria.

I know there's not much we can do for AD at the moment, short of prevention, but are there any diagnostic and management implications here?

I find huge implications, given the diagnostic odyssey these patients go through. In terms of communicating with the public and providers, I believe that is of primary importance to recognize these cases when they present early, give patients the proper diagnosis and proper counseling, and get them set up with the proper support structure and resources that are available. These people spend years bouncing around to different providers and struggling at work, losing their jobs, and not knowing why. The therapeutic value of actually recognizing it early can't be overappreciated.

The pharmacologic management is identical to that of typical AD. Given that there haven't been any dedicated clinical trials of this phenotype, we don't know whether other therapeutic approaches would be more beneficial because it hasn't been studied. There's also a growing body of literature drawn from the pathologic studies that indicate that people with hippocampal-sparing AD may also benefit more from acetylcholinesterase inhibitors than those with typical AD. Those treatments may be even more important to start early in these cases, but that's apparently unknown.

I can see how misdiagnosis would traditionally have been a big problem. What other syndromes is dysexecutive AD often diagnosed as?

The two most common misdiagnoses would be psychiatric and behavioral variant frontotemporal dementia. Psychiatric diagnoses were probably the most common early on. Then, as patients proceeded along the provider chain, they'd get the potential diagnosis of frontotemporal dementia or AD. You would see patients with this condition who were undergoing psychoanalysis for over a year, and obviously that's not going to help.

What's next for you? Do you have any follow-up research planned in this area?

We want to study the neurodynamics of executive function at the laminar level, using layer-fMRI to try to understand what's unique about the neurophysiology of this condition relative to typical AD. We want to study the epidemiology and get a good understanding of the prevalence and incidence rates. We also are a site for LEADS, a study looking at disease progression in early-onset AD.

Do you have any final messages for practicing neurologists about atypical AD?

Identifying atypical phenotypes and having a clear case definition will help us with early and accurate diagnosis and treatment, which should have direct implications for patient outcomes. This is important.

These patients may not have any appreciable atrophy on brain MRI, especially in the hippocampus, and symptoms may be quite subtle. If you look closely at the parietal lobe, you may see atrophy, but sometimes it's even subtle there. However, a fluorodeoxyglucose PET scan of the brain is almost always abnormal, which is a clear indication that there could be an underlying neurodegenerative disease rather than a psychiatric condition causing the patient's trouble with working memory.

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