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NeuroVoices: Lynn Bekris, PhD, on Future Research for sTREM2, GFAP, and Immunotherapies in Alzheimer Disease

SAP Partner | <b>Cleveland Clinic</b>

The molecular biologist at the Cleveland Clinic Lerner Research Institute discussed the unanswered questions regarding biomarkers sTREM2 and GFAP, and the role they play in Alzheimer pathology.

This is part 2 of a 2-part interview. Click here for part 1.

In recent years, there has been an increased effort to study glial fibrillary acidic protein (GFAP), an astrocyte activity marker, and its relationship with neurodegeneration and Alzheimer disease (AD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a myeloid cell activity marker, has been genetically linked to AD risk as well. At the 2022 Alzheimer’s Association International Conference (AAIC), July 31 to August 4, in San Diego, California, a group of investigators from Cleveland Clinic presented work on the differences in cerebrospinal fluid (CSF) levels of both sTREM2 and GFAP in AD and AD-related dementias (ADRD).1

Led by Lynn Bekris, PhD, the findings suggested that inflammatory factors such as CSF sTREM2, GFAP, and α-synuclein were altered in both AD and dementia with Lewy bodies (DLB). Additionally, there were alterations in the sTREM2/GFAP ratio in DLB, and a strong positive correlation between sTREM2 and α-synuclein for all patients—which included AD, DLB, mild cognitive impairment, Parkinson disease—except for cognitively normal controls. The findings raise the question about future drug developments and whether targeting certain immunopathologic areas to seek immune response should be more heavily considered.

In a new iteration of NeuroVoices, NeurologyLive® sat down with Bekris to discuss the future directions hinted at by the results. Bekris, a molecular biologist at the Cleveland Clinic Lerner Research Institute, detailed the remaining questions from the research, the need to validate, why sTREM2/GFAP ratio is important, and how these findings may impact future treatment decisions.

NeurologyLive®: How can you and your colleagues expand on these findings?

Lynn Bekris, PhD: We are hoping to expand on this by looking at more of the pathology relationship with sTREM2 and GFAP. We can look at stages that way. You mentioned stage of the disease, we can look at the [ATN, or “Amyloid, Tau, and Neurodegeneration”] framework. We can look at the levels of amyloid and tau and neurodegeneration, and determine when this ratio, for example, might be most altered. Is it altered when amyloid is positive, but when tau is negative? Is it altered when people have α-synuclein at a highly elevated level? Which we would think would be true because of the relationship between α-synuclein and sTREM2, but we don't know that yet. We hope to look at that, but also because sTREM2 a relatively new assay.

Additionally, we want to evaluate the performance of sTREM2 and α-synuclein because it has not really performed super well in cerebrospinal fluid. We also want to expand the study to look at potentially seed assays. As α-synuclein aggregates, we can use another assay to look at it. We can see if an individual has high seeding activity using an assay called RT quick. That's something else we'd like to do. We just want to dive into the details a little bit more before we can be confident that what we are seeing is real. And we also want to replicate it in other cohorts, which is something we always have to do in science.

Should GFAP be more closely observed when formulating clinical trials?

I am not a clinical trialist or physician, so these kinds of questions are kind of hard for me to answer, but I know that people are looking at sTREM2 in clinical trials. I don't know so much about GFAP, but in general, I think the immune response is a therapeutic target. There are a few clinical trials that are looking at sort of the general immune response. Essentially anti-immunological therapies. This information will help us home in on the particulars of the immune response so that we can determine if these disorders are good candidates for immunotherapies. A lot of Alzheimer's disease clinical trials are focused on amyloid, but it looks like a lot of us are seeing that the inflammatory response is also involved. We still have a lot to do to determine what type of immune response is happening in each one of these disorders.

Considering that sTREM2 is a myeloid cell activity marker and GFAP is an astrocyte activity marker, why was it important to look at the ratio between the two?

It’s important because we have observed in autopsy studies that there's astrogliosis in these disorders, and we also know now that microglia are very important. There are, two kinds of camps where people are studying astrocytes and people are studying microglia. Whereas is if we have markers that are reflecting those different activities, for example, GFAP and sTREM2, then we could perhaps use a ratio to understand which individuals, in a more precise way, are exhibiting a more astrocytic response versus a myeloid response. That's why we wanted to look at the ratio to see if there was a significant difference between these groups, and it looks like there is, so I think that's pretty interesting.

Transcript was edited for clarity. Click here for more NeuroVoices.

REFERENCE
1. Jain L, Khrestian M, Tuason ED, et al. Cerebrospinal fluid glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in Alzheimer’s disease and related dementias (ADRD). Presented at: 2022 Alzheimer’s Association International Conference; July 31 to August 4; San Diego, CA. 68332