ObjectiveInflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively.MethodsStudies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges’s g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity.ResultsA total of 170 studies were included in the meta-analysis and systematic review, which demonstrated increased peripheral levels of high-sensitivity C reactive protein (Hedges’s g 0.281, p<0.05), interleukin-6 (IL-6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1-antichymotrypsin (α1-ACT) (1.217, p<0.005), IL-1β (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL-10 (0.434, p<0.05), monocyte chemoattractant protein-1 (MCP-1) (0.798, p<0.005), transforming growth factor-beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL-40 (0.849, p<0.001), α1-ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin-like protein-1 (VILIP-1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL-6 (0.129, p<0.05) and MCP-1 (0.779, p<0.05) and lower levels of IL-8 (−1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL-40 (0.373, p<0.05), VILIP-1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI.ConclusionSignificantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

Background Inflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD and MCI quantitatively. Method Studies reporting concentrations of peripheral or cerebrospinal fluid (CSF) markers were included, and eligible data on AD, MCI and control were extracted. Pooled Hedges's g was adopted to illustrate comparisons, and various confounding factors were used to explore sources of heterogeneity. Result A total of 170 studies were included in the meta‐analysis and systematic review, which demonstrated increased peripheral levels of high‐sensitivity C reactive protein (Hedges's g 0.281, p<0.05), interleukin‐6 (IL‐6) (0.429, p<0.005), soluble tumour necrosis factor receptor 1 (sTNFR1) (0.763, p<0.05), soluble tumour necrosis factor receptor 2 (sTNFR2) (0.354, p<0.005), alpha1‐antichymotrypsin (α1‐ACT) (1.217, p<0.005), IL‐1β (0.615, p<0.05) and soluble CD40 ligand (0.868, p<0.005), and CSF levels of IL‐10 (0.434, p<0.05), monocyte chemoattractant protein‐1 (MCP‐1) (0.798, p<0.005), transforming growth factor‐beta 1 (1.009, p<0.05), soluble triggering receptor expressed on myeloid cells2 (sTREM2) (0.587, p<0.001), YKL‐40 (0.849, p<0.001), α1‐ACT (0.638, p<0.001), nerve growth factor (5.475, p<0.005) and visinin‐like protein‐1 (VILIP‐1) (0.677, p<0.005), in AD compared with the control. Higher levels of sTNFR2 (0.265, p<0.05), IL‐6 (0.129, p<0.05) and MCP‐1 (0.779, p<0.05) and lower levels of IL‐8 (‐1.293, p<0.05) in the periphery, as well as elevated concentrations of YKL‐40 (0.373, p<0.05), VILIP‐1 (0.534, p<0.005) and sTREM2 (0.695, p<0.05) in CSF, were shown in MCI compared with the control. Additionally, increased peripheral sTNFR1 (0.582, p<0.05) and sTNFR2 (0.254, p<0.05) levels were observed in AD compared with MCI. Conclusion Significantly altered levels of inflammatory markers were verified in comparison between AD, MCI and control, supporting the notion that AD and MCI are accompanied by inflammatory responses in both the periphery and CSF.

Background: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a general biomarker for axonal damage.Methods: This genome-wide association study (GWAS) consisted of 169 mild cognitive impairment (MCI) subjects and 94 cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model. The novel single nucleotide polymorphisms (SNPs) identified by GWAS were further examined for their correlation with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively. Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD and from MCI to AD among populations with different genotypes.Results: Two novel SNPs (rs465401 and rs460420), both near the ADAMTS1 gene on chromosome 21, showed genome-wide significant associations with CSF NFL. The minor allele (A) of rs465401 was also associated with higher CSF total tau (t-tau) levels, lower amyloid-β (Aβ) levels as well as greater longitudinal change in both Aβ and t-tau among the CN group. Furthermore, the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes. Conclusions:We found that two SNPs (rs465401 and rs460420) were associated with CSF NFL in non-demented elders. The associations identified in this study may make the SNPs and ADAMTS1 ideal candidates for future genetic studies on aging and neurodegenerative disorders.