Fig. 2: Summary of biomarker studies and overview of key outcomes of the longitudinal studies captured by SLR.

Bubble charts in A, B, and C summarize biomarkers studies of YKL-40, sTREM2, and GFAP respectively. For each of the comparisons within the study, the position of the bubble corresponds to the ratio of mean/median values of biomarker with respect to the control group. If the bubble is on the left of the red dotted line (ratio < 1), biomarker levels are higher in the control group; if the bubble is on the right of the red dotted line (ratio > 1), biomarker levels are higher in the comparator group. The statistical significance of the differences in the mean/median values of biomarker levels between control and comparator group is denoted by the color and size of the bubble, and the numbers in the center of the bubbles (or to the side) denote the sample size of the groups that were compared in the study. D shows the longitudinal studies captured by SLR for fluid biomarkers of neuroinflammation, along with follow-up time and the main outcome of the study. Green arrows depict the studies that showed relationships between the change in biomarker levels and cognitive decline or brain pathology over time, while red arrows indicate studies that could not show such relationships. Note: The term “MCI” is “all-cause MCI”, unless otherwise stated. Presence (+) or absence (−) of abnormal biomarkers of amyloid (A), tau (T), and neurodegeneration (N) as per A−T−N classification. Aβ amyloid-β pathology, AD Alzheimer’s disease, AUC area under the ROC curve, CCL2 C-C motif chemokine ligand 2, CCL5 C-C motif chemokine ligand 5, CDR clinical dementia rating scale, CI cognitively impaired, CSF cerebrospinal fluid, CU cognitively unimpaired, ELISA enzyme-linked immunosorbent assay, GFAP glial fibrillary acidic protein, HR hazard ratio, IL interleukin, MCI mild cognitive impairment, MCI-AD MCI due to AD, PET positron emission tomography, ROC receiver operating characteristic, SLR systematic literature review, sTREM2 soluble triggering receptor expressed on myeloid cells 2, TNF-α tumor necrosis factor alpha, YKL-40 chitinase-3-like protein 1.