Carney Institute (CI): Tell us about this grant.

Ted Huey (TH): The title of the grant is “The Genetics of Neuropsychiatric Symptoms in Alzheimer's Disease in Populations of Diverse Ancestry.” 

Neuropsychiatric Symptoms (NPS) include non-cognitive symptoms such as aggression, psychosis, anxiety, apathy, depression and sleep disturbances. 85% of Alzheimer’s disease (AD) patients wrestle with NPS which are associated with significantly increased suffering, accelerated decline, increased cost and increased out-of-home placement. They also have a deep effect on caregivers, often even more than typical dementia symptoms of memory and other impairments. 

However, our understanding of the causes of NPS is pretty shallow and the available treatments aren’t terribly effective. This knowledge gap is particularly severe in underserved racial and ethnic groups such as Hispanics and African Americans; populations that have historically had limited studies, despite a higher incidence of AD and a higher overall rate of NPS. 

The National Institute on Aging (NIA) and the National Institutes of Health (NIH) initiated the Alzheimer Disease Sequencing Project (ADSP) and its Follow-Up-Study (ADSP-FUS) to better understand and enhance our understanding of the causes of Alzheimer’s and related diseases in underserved populations. Yet, no concerted effort is being made to collect, harmonize or analyze associated neuropsychiatric symptoms data within these samples. 

This is a major oversight, since having a better understanding of the genetic role of NPS plays in AD –  as informed by ancestral background – is key to understanding and treating the disease. This is particularly urgent as research shows that the genetic contribution to NPS in AD  is around 30~60%.

To address these shortcomings, our study will harmonize and utilize NPS data within the existing work of the Alzheimer Disease Sequencing Project Follow-Up-Study. Using over 80,000 previously collected samples, we will assess the role of ancestry in NPS genetic risk by identifying and characterizing population specific determinants, drug pathways and genetic characteristics underlying NPS in AD. 

Once we’ve refined this data, we will make it user-friendly and accessible to all qualified investigators,

CI:  Does the geography of the respondents play any role in the study?

TH: The lion’s share of these individual samples come from the U.S., but other cohorts are represented including Africa and Asia. As the research becomes more nuanced, we’re beginning to focus more on this idea of ancestry as a factor that can be quantified with genetic analyses  without relying just on self-identification.

CI: Within these data sets, are you able to consider broader sociological and economic factors?

TH: This is one of the more challenging elements for the study to consider since biological and sociological impacts are not mutually exclusive. When one group of respondents is more frequently diagnosed with NPS symptoms than another – aggression for example – how much of this diagnosis and interpretation of behavior is the result of racism or bias? What about differences in social determinants of health including diet, support structure, etc.?

So, I see this project as the first step, which is to assess the biological side of NPS in AD, whereas the end goal is to understand both the biological and the sociological sides of these symptoms.

CI: Tell us more about why harmonizing this data is so important.

TH: There is more variability in NPS than cognitive symptoms of AD. We know that the vast majority of AD patients will have memory problems in a predictable way, but non-cognitive symptoms are very variable. We still don't know why one person gets psychosis and another person doesn't; why does someone get depressed, and another person doesn't. 

This variability suggests that looking at the genetic bases of NPS could be fruitful which, again, really hasn't been done in the past. If we can identify the genetic basis of NPS, we can better target drugs and other assistive therapies.

One aim we have also is to compare our findings to findings from other primary psychiatric disorders. For example, is there any genetic overlap between depression when someone has Alzheimer's disease vs. major depressive disorder? How are they similar? How are they different? This suggests that looking at the genetic variance could be fruitful which, again, really hasn't been done in the past. If we can identify the genetic basis, we can better target drugs and other assistive therapies.

We have a committee based largely here at Brown and at Butler where we adjudicate the fitness of the data and confirm its veracity and usability, such that it will be useful to investigators who are interested in these questions.  We really want people to use the data so the phenotype harmonization we are doing at Brown and the whole genome sequencing of these samples will be made available to the scientific community through the ADSP and its Follow-Up-Study. 

CI: Can you talk about how this research might impact care in the clinical setting?

TH: The course of care currently available for AD patients struggling with NPS is largely based on psychiatric medications that were developed for psychiatric or primary psychiatric disorders several decades ago. These treatments frequently don't work and they often have detrimental side effects. We think that new therapies based on a better understanding of the genetics could address the symptoms in entirely new ways.

While some may say that treating symptoms of the disease is not of much value, particularly in light of new disease modifying therapies like anti-amyloid treatments, it can still improve patient’s lives as well as the lives of caregivers. Additionally, if you find something that makes people symptomatically better, it begs the question “are you altering the course of disease itself in any way in a more permanent way?” So, I think it has the potential to be ait's kind of a win-win.

CI: As a scientist and clinician who works at both Brown and Butler Hospital, can you talk a bit about the collaborative nature of the research powering this grant?

TH: My particular interest is assessment and phenotyping of these kinds of symptoms, but we have a larger group here at Butler and at Brown who act as an “adjudication committee” of sorts for this study. We have neuropsychologists, psychiatrists and statisticians, experts in dementia, genetics, and ancestry. Efforts like this one do, indeed, “take a village,” and Brown and Butler have provided an ideal environment to perform this type of research.