Introduction: Neuroinflammation is associated with both early and late stages of the pathophysiology of Alzheimer's disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis in presymptomatic stages, monitoring, and disease prognosis. This systematic literature review (SLR) aimed to identify fluid biomarkers for neuroinflammation related to clinical stages across the AD continuum and examined long-term outcomes associated with changes in biomarkers.
Methods: The SLR was conducted per the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We used PubMed®, Embase®, and Cochrane Collaboration databases to search for articles in English (between 2012 and 2022) on AD or mild cognitive impairment due to AD, using "neuroinflammation" or other "immune" search strings. Two independent reviewers screened titles and examined data from full-text articles for the SLR.
Results: After the initial screening, 54 studies were prioritized for data extraction based upon their relevance to the SLR research questions. Nine studies for YKL-40, seven studies for sTREM2, and 11 studies for GFAP examined the relationship between the neuroinflammatory biomarkers and the clinical stage of the disease. Nine longitudinal studies further explored the association of fluid biomarkers with long-term clinical outcomes of disease. Cerebrospinal fluid (CSF) levels of YKL-40 were elevated in patients with AD dementia, while CSF sTREM2 levels were more strongly associated with preclinical and early symptomatic stages of AD. Plasma GFAP levels remained consistently elevated both in patients with AD dementia and individuals in preclinical stages with β-amyloid pathology. Longitudinal changes in plasma GFAP appeared to be predictive of cognitive decline in patients over time.
Discussion: Neuroinflammatory biomarkers are associated with AD progression. More longitudinal studies in the preclinical and MCI stages of AD are needed to validate fluid biomarkers for diagnosis, disease monitoring, and prognosis in clinical practice.
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