TREM2 may have protective effect in Alzheimer’s disease
By Shreeya Nanda, medwireNews Reporter
Researchers have identified an association between faster rates of increase of TREM2 levels in soluble cerebrospinal fluid (CSF) and slower progression of several markers of disease evolution in participants of the Dominantly Inherited Alzheimer Network (DIAN), which they say points to a likely protective effect of TREM2 during the early pathogenesis of Alzheimer’s disease.
“These findings support ongoing efforts to develop TREM2-boosting therapies as disease-modifying treatments for Alzheimer’s disease and suggest an early window for therapeutic intervention”, say Estrella Morenas-Rodríguez (Hospital Universitario 12 de Octubre, Madrid, Spain) and co-authors in The Lancet Neurology.
They explain that TREM2 is a protein associated with microglial function and inflammation, and rare mutated versions are associated with an increased risk of Alzheimer’s disease.
The researchers used a novel immunoassay to assess cleaved soluble TREM2 levels in CSF samples collected annually or every 2 years from 239 DIAN participants enrolled between 2009 and 2019. One hundred of the participants were presymptomatic carriers of pathogenic variants in the PSEN1, PSEN2 or APP genes, 48 were symptomatic carriers and the remaining 91 were noncarriers.
The team found that a faster annual rate of increase of soluble TREM2 levels was associated with a significantly reduced rate of decrease of amyloid-β (Aβ)42 in CSF samples from presymptomatic carriers and a significantly reduced rate of increase of Pittsburgh compound B–positron emission tomography (PiB–PET) uptake in symptomatic carriers.
Further investigation showed that among presymptomatic carriers, there were contrasting associations between CSF Aβ42 levels and PiB–PET uptake depending on whether the rates of increase of soluble TREM2 were above or below the median, say Morenas-Rodríguez and colleagues.
They additionally identified a correlation between greater annual rates of increase of phosphorylated-tau in CSF and increased PiB–PET uptake in presymptomatic carriers with annual rates of increase of soluble TREM2 that were below the median. But there was no such correlation among those with rates above the median.
Finally, assessment of neuroimaging and cognitive outcomes in presymptomatic carriers showed a significant correlation between greater rates of soluble TREM2 increase and slower cortical shrinkage in the precuneus as well as with slower progression of cognitive decline.
Taken together, these results suggest “a potential protective role of TREM2 function on amyloid-dependent tau pathology, in line with results in mouse models”, say the researchers.
The authors of a related commentary agree that “these new data support the hypothesis that TREM2 might have a protective function in the early pathogenesis of Alzheimer’s disease and support a rationale for the development of TREM2-targeted therapeutics.”
But they point out that despite the longitudinal study design, “the associations identified are, at their core, correlational and causation cannot be inferred from this study alone.”
Denis Smirnov and Douglas Galasko, both from UC San Diego in La Jolla, California, USA, also note that the “study did not identify the mechanisms that might underlie variable soluble TREM2 responses in CSF that could provide guidance towards personalised therapeutic approaches.”
And they conclude: “Continued laboratory studies with direct manipulation of TREM2 activity will be essential, although the limitations of animal models might mean that human trials will be the ultimate test of the authors’ hypotheses, and the present study provides a roadmap towards that goal.”
News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group
Lancet Neurol 2022; 21: 329–341
Lancet Neurol 2022; 21: 297–298