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Published on: September 3, 2021
sTREM2 is associated with amyloid-related p-tau increases and glucose hypermetabolism in Alzheimer's disease
Davina Biel1, Marc Suárez-Calvet2,3,4,5, Paul Hager6
1Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
Abstract:
Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta-amyloid (CSF Aβ1-42 ) and late-stage fibrillary Aβ pathology (amyloid-PET centiloid), as well as sTREM2, p-tau181 , and FDG-PET. To determine disease stage, we stratified participants into early Aβ-accumulators (Aβ CSF+/PET-; n = 70) or late Aβ-accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau181 increases and higher sTREM2 was associated with FDG-PET hypermetabolism. In late Aβ-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau181 and glucose hypometabolism. Our findings suggest that a TREM2-related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau181 increases in earliest AD.
Insights
Microglial activation, indicated by TREM2, follows early amyloid pathology in Alzheimer's disease (AD). This response is linked to inflammation and tau increases, suggesting a role in early AD progression.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Microglial activation is an early event in Alzheimer's disease (AD), with debated roles in disease progression.
- Soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) can indicate microglial activation.
- Understanding microglial responses across AD stages is crucial for therapeutic development.
Purpose of the Study:
- To investigate disease stage-dependent drivers of microglial activation using CSF sTREM2.
- To determine the downstream consequences of microglial activation on Alzheimer's disease progression.
- To link amyloid pathology, microglial response, tau pathology, and brain metabolism across AD stages.
Main Methods:
- Analysis of 402 participants stratified by amyloid-beta (Aβ) accumulation stages (early and late).
- Utilized CSF Aβ1-42, amyloid-PET centiloid, CSF sTREM2, CSF p-tau181, and FDG-PET imaging.
- Examined associations between biomarkers and metabolic activity across different disease stages.
Main Results:
- In early AD, higher amyloid burden correlated with increased sTREM2 and p-tau181.
- sTREM2 mediated the link between amyloid burden and p-tau181 increases, and was associated with hypermetabolism.
- In late AD, sTREM2 was linked to hypometabolism, independent of amyloid burden.
Conclusions:
- A TREM2-mediated microglial response is associated with early amyloid fibrillization in Alzheimer's disease.
- This microglial response may drive inflammatory changes and subsequent tau pathology in early AD.
- Microglial activation dynamics and metabolic consequences differ between early and late stages of AD.
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