sTREM2 is associated with amyloid‐related p‐tau increases and glucose hypermetabolism in Alzheimer's disease

• Published in: EMBO molecular medicine Vol. 15; no. 2; pp. e16987 - n/a
• Main Authors: Biel, Davina, Suárez‐Calvet, Marc, Hager, Paul, Rubinski, Anna, Dewenter, Anna, Steward, Anna, Roemer, Sebastian, Ewers, Michael, Haass, Christian, Brendel, Matthias, Franzmeier, Nicolai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.02.2023; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: age; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides; beta-amyloid; Biomarkers; Brain; Cross-Sectional Studies; deposition; drives; EMBO02; EMBO27; Fibrillogenesis; Fluorodeoxyglucose F18; Glucose; glucose metabolism; Humans; Inflammation; Metabolism; Microglia; Neurodegeneration; Neurodegenerative diseases; Neurologi; Neurology; p-tau; Pathology; patterns; Research & Experimental Medicine; sTREM2; Tau protein; tau Proteins; variability; β-Amyloid; sTREM2; beta‐amyloid; Alzheimer's disease; glucose metabolism; p‐tau; beta-amyloid; p-tau
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.202216987

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 Aβ 1‐42 ) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau 181 , 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‐tau 181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau 181 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‐tau 181 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‐tau 181 increases in earliest AD. Synopsis In Alzheimer's disease (AD), microglial activation has been linked to both detrimental and protective effects on disease progression. This study used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. In participants with early beta‐amyloid (Aβ) accumulation, higher amyloid‐PET was associated with higher cross sectional/longitudinal CSF sTREM2 and CSF p‐tau 181 levels. In participants with early Aβ accumulation, sTREM2 mediated the association between amyloid‐PET and CSF p‐tau 181 increases. Higher CSF sTREM2 levels were associated with FDG‐PET glucose hypermetabolism in early Aβ accumulation but with glucose hypometabolism in late Aβ accumulation. Graphical Abstract In Alzheimer's disease (AD), microglial activation has been linked to both detrimental and protective effects on disease progression. This study used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression.