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

Joana B Pereira; Shorena Janelidze; Olof Strandberg; Christopher D Whelan; Henrik Zetterberg; Kaj Blennow; Sebastian Palmqvist; Erik Stomrud; Niklas Mattsson-Carlgren; Oskar Hansson

doi:10.1038/s43587-022-00310-z

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

Nat Aging. 2022 Dec;2(12):1138-1144. doi: 10.1038/s43587-022-00310-z. Epub 2022 Nov 28.

Authors

Joana B Pereira^{1

2}, Shorena Janelidze³, Olof Strandberg³, Christopher D Whelan⁴, Henrik Zetterberg^{5

6

7

8

9}, Kaj Blennow^{5

6}, Sebastian Palmqvist^{3

10}, Erik Stomrud^{3

10}, Niklas Mattsson-Carlgren^{3

11

12}, Oskar Hansson^{13

14}

Affiliations

¹ Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institute, Huddinge, Sweden. joana.pereira@ki.se.
² Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, Sweden. joana.pereira@ki.se.
³ Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, Sweden.
⁴ Biogen Research and Development, Cambridge, MA, USA.
⁵ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
⁷ UK Dementia Research Institute at UCL, London, UK.
⁸ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁹ Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
¹⁰ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
¹¹ Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
¹² Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
¹³ Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, Sweden. Oskar.Hansson@med.lu.se.
¹⁴ Memory Clinic, Skåne University Hospital, Malmö, Sweden. Oskar.Hansson@med.lu.se.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / pathology
Amyloid
Amyloidogenic Proteins
Cognitive Dysfunction* / pathology
Humans
Microglia / pathology
c-Mer Tyrosine Kinase
tau Proteins

Substances

tau Proteins
c-Mer Tyrosine Kinase
Amyloid
Amyloidogenic Proteins