Adam Brickman, PhD, Discusses Alzheimer-Related Pathology in the Context of Down Syndrome

In this podcast, Dr Brickman discusses his recent study, which demonstrated the prevalence of cerebrovascular disease among individuals with Down syndrome, and indicated that cerebrovascular disease may be a "core feature" of Alzheimer disease. A full transcript is provided below.

Discover more insights from your peers in our Alzheimer Disease Excellence Forum.

Adam Brickman, PhD, is a professor of neuropsychology at Columbia University in the Department of Neurology and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain.

Reference:
Lao PJ, Gutierrez J, Keator D, et al. Alzheimer‐related cerebrovascular disease in Down syndrome. Ann Neurol. 2020;88(6):1165-1177. doi:10.1002/ana.25905

Transcript:

Christina Vogt: Hello, everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today I'm joined by Dr Adam Brickman, who is professor of neuropsychology at Columbia University in the Department of Neurology and in the Taub Institute for Research on Alzheimer's disease and the Aging Brain.

Today we are going to talk about his recent study, “Alzheimer‐Related Cerebrovascular Disease in Down Syndrome,” which was published in Annals of Neurology.

Thank you for joining me today, Dr Brickman. First, in your study, you and your colleagues noted that adults with Down syndrome develop Alzheimer's disease pathology by their fifth decade of life. Could you elaborate on this?

Dr Adam Brickman: Sure. It's been well-known for a long time at this point, even back to the days of Dr Alzheimer himself, that individuals with Down syndrome who, at the time, lived into their 40s had the characteristic pathological stigmata of Alzheimer's disease, including amyloid plaques and neurofibrillary tangles.

That's been well established. Typically, the pathology is there by their 40s, and the symptoms of Alzheimer's disease, the dementia syndrome typically manifests by their 60s. This is probably due to the triplication of the 21st chromosome, which is where the amyloid precursor protein gene lies.

Christina Vogt: The results of your study imply that cerebrovascular disease may be a core feature of Alzheimer's disease rather than solely a comorbidity. Could you discuss this in more detail?

Dr Brickman: Sure. We've known from individuals with late-onset Alzheimer's disease from the general population that we often see markers of cerebrovascular disease either on imaging or in pathological studies. In fact, it's more common for older adults with clinical Alzheimer's disease to have vascular, cerebrovascular lesions than not.

The general idea has been that cerebrovascular disease is common in aging, and it's a comorbidity with Alzheimer's disease, and it contributes additively to the syndrome of dementia that we see in Alzheimer's disease.

People with genetic forms of Alzheimer's disease like people with presenilin-1 or -2 mutations, or in this case, people with Down syndrome offer us an opportunity to look at whether cerebrovascular disease markers are increased without the confound of vascular risk factors.

That said, it's not confounded in these populations because people with Down syndrome typically get Alzheimer's disease a lot younger than the general population. Also, interestingly, they tend to have very low rates of common vascular risk factors like hypertension and type 2 diabetes.

This gave us an opportunity to ask the question whether we see increased markers of cerebrovascular disease among individuals with Down syndrome, which in and of itself would be surprising, given that they have very few vascular risk factors.

Then we could also ask the question about whether we see increased cerebrovascular disease markers as they develop or with the diagnosis of clinical Alzheimer's disease and its preclinical form of mild cognitive impairment.

What we found is we measured a bunch of different cerebrovascular markers using magnetic resonance imaging or MRI. We found, first of all, that there's quite a bit of evidence of cerebrovascular disease in the form of white matter hyperintensities, cerebral microbleeds in large perivascular spaces, and even Frank infarcts.

These lesions tended to increase with the diagnosis of mild cognitive impairment, and then with clinical possible or definite Alzheimer's disease.

Christina Vogt: What implications could these findings have for practice going forward, if confirmed or replicated?

Dr Brickman: It's a great question. The first thing is, we do have to replicate and understand what are some of the driving forces of cerebrovascular disease in the context of Down syndrome.

Because they tend to have low rates of the typical vascular risk factors like hypertension and type 2 diabetes, we have to ask the question why is it that we see these increased cerebrovascular disease markers?

An important implication is that it points to a different avenue of potential treatment for Alzheimer's disease. Based on our findings, starting tomorrow or today, I wouldn't necessarily recommend changing how we treat people with Down syndrome. However, it does have longer-term implications for understanding different pathways for therapeutic options in Alzheimer's disease.

We have to understand why is it that we're observing increased cerebrovascular disease markers in Down syndrome, and whether something about the mediators of those increased amounts of cerebrovascular disease might point to new therapeutic avenues in treating Alzheimer's disease in the context of Down syndrome, and possibly or hopefully, in the general population as well.

Christina Vogt: What areas of future research are still needed in this field?

Dr Brickman: There are a lot of important follow-up questions that we have. First of all, we want to understand, when in the life course do we start to see an emergence of cerebrovascular disease in Down syndrome?

All of the participants included in the current study were over age 40, so we want to first expand the sample. We're doing that to look across the adult lifespan and see if there's an inflection point where we start to see an emergence of cerebrovascular disease.

Second of all, we need to understand, what are the mediators of the cerebrovascular disease markers that we're seeing in the context of Down syndrome?

We suspect that inflammation is playing a role. We're currently looking at different markers, plasma markers for inflammatory changes, and we also need to understand whether the cerebrovascular disease markers that we're measuring are interacting with other biomarkers of Alzheimer's disease.

There's a lot to do, and in the longer term we can start to formulate or think about strategies for addressing or treating or preventing cerebrovascular disease. That's a potential therapeutic avenue.

Christina Vogt: Lastly, what key takeaways about this topic do you hope to leave with neurologists, neurology providers, and researchers?

Dr Adam Brickman:  There are a lot of things to consider. In individuals who are practitioners, who are treating or evaluating people with Down syndrome, it's always important to understand that Alzheimer's disease is a fundamental part of Down syndrome. Just as much attention as we pay to general medical health, we should also be evaluating cognitive health and dementia status among our patients with Down syndrome.

Second of all, it's important to start thinking about, what are some of the contributors for cognitive changes in Down syndrome? An MRI scan isn't always warranted in adults with Down syndrome, but sometimes if there's concern about cognitive decline, an MRI scan might reveal that there are cerebrovascular changes that might be contributing.

If there are, in individual cases, ways of addressing those cerebrovascular changes—those should be considered clinically.

Christina Vogt: Thanks again for joining me today, Dr Brickman. For more podcasts like this, visit neurologylearningnetwork.com.