Microglial activation protects against accumulation of tau aggregates in nondemented individuals with underlying Alzheimer’s disease pathology

• Published in: Nature aging Vol. 2; no. 12; pp. 1138 - 1144
• Main Authors: Pereira, Joana B., Janelidze, Shorena, Strandberg, Olof, Whelan, Christopher D., Zetterberg, Henrik, Blennow, Kaj, Palmqvist, Sebastian, Stomrud, Erik, Mattsson-Carlgren, Niklas, Hansson, Oskar
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2022; Nature Publishing Group US
• Subjects: Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Amyloidogenic Proteins; Basic Medicine; c-Mer Tyrosine Kinase; Cognitive Dysfunction - pathology; Humans; Letter; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Microglia - pathology; Neurosciences; Neurovetenskaper; Pathology; tau Proteins
• ISSN: 2662-8465; 2662-8465
• DOI: 10.1038/s43587-022-00310-z

The role of microglia in tau accumulation is currently unclear but could provide an important insight into the mechanisms underlying Alzheimer’s disease (AD) 1 . Here, we measured the microglial marker soluble TREM2 and the disease-associated microglial activation stage 2 markers AXL, MERTK, GAS6, LPL, CST7, SPP1 and CSF1 in nondemented individuals from the Swedish BioFINDER-2 cohort who underwent longitudinal tau-positron emission tomography (PET), amyloid-PET and global cognitive assessment. To assess whether baseline microglial markers had an effect on AD-related changes, we studied three sub-groups of individuals: 121 with evidence of amyloid-PET pathology (A + ), 64 with additional evidence of tau-PET pathology (A + T + ) and 159 without amyloid- or tau-PET pathology (A − T − ). Our results showed that increased levels of TREM2 were associated with slower amyloid accumulation in A + individuals in addition to slower tau deposition and cognitive decline in A + T + subjects. Similarly, higher levels of AXL, MERTK, GAS6, LPL, CST7 and CSF1 predicted slower tau accumulation and/or cognitive decline in the A + T + group. These findings have important implications for future therapeutic strategies aiming to boost microglial protective functions in AD.