The Role of Neuroinflammation in Alzheimer's Disease: A Systematic Literature Review
Michael Heneka1, Serge Gauthier2, Sagar Anil Chandekar3, Julie Hviid Hahn-Pedersen3, Marie Bentsen3, Henrik Zetterberg4
1Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, 2AD and Related Disorders Research Unit, McGill Center for Studies in Aging, Departments of Neurology & Neurosurgery, Psychiatry, and Medicine at McGill University, 3Novo Nordisk A/S, 4Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital; Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square; UK Dementia Research Institute at University College London; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay; Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin–Madison
Objective:
This systematic literature review (SLR) aimed to investigate the role of neuroinflammation in AD and explore the association of neuroinflammation with AD disease progression.
Background:
Several mediators of neuroinflammation can serve as therapeutic targets for Alzheimer’s disease (AD) and as prognostic biomarkers.
Design/Methods:
A SLR was conducted in 2023 using MEDLINE®, Embase®, and PsycInfo® databases to identify English-language articles from 2012 on AD including mild cognitive impairment (MCI). Two independent reviewers screened titles and examined full-text records for relevance.
Results:
The SLR identified 3669 articles, of which 114 were included, and detailed data were extracted from 56. Cerebrospinal fluid (CSF) inflammatory biomarkers – YKL-40, sTREM2, and GFAP were identified to have a key role in AD neuroinflammation. Significantly higher levels of CSF YKL-40, CSF sTREM2, and CSF GFAP were found in patients with dementia due to AD compared with cognitively unimpaired control subjects. CSF sTREM2 changes were found to be sensitive to preclinical stages of AD and showed prognostic value in predicting rate of cognitive decline in AD. CSF YKL-40 levels were higher in the dementia stage of AD and increased longitudinally in patients with all-cause MCI and AD patients with dementia; highest baseline levels of CSF YKL-40 in subjects with all-cause MCI predicted progression to dementia due to AD. In cognitively unimpaired/people with subjective cognitive decline, higher baseline levels of serum or plasma GFAP predicted steeper rate of cognitive decline and clinical progression to AD dementia. In AD patients with dementia, higher levels of plasma GFAP were associated with greater change in MMSE score and poor cognitive outcome during follow-up.
Conclusions:
Evidence from fluid biomarkers consolidates the role of neuroinflammation in pathophysiology of AD and supports clinical use of GFAP for prognostic purpose as recommended in the draft NIA-AA Revised Criteria for Diagnosis and Staging of Alzheimer's Disease 2023 guidelines.