Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer’s disease diagnosis and therapeutic targets
Bibliographic record
Abstract
Amyloid-beta clearance plays a key role in the pathogenesis of Alzheimer's disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer's disease. The methodological quality of the studies was assessed via the Newcastle‒Ottawa Scale. Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer's disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16-0.47, P < 0.001, I2 = 78.4%; SMD = 1.24, 95% CI: 0.01-2.48, P = 0.048, I2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35-1.66, P = 0.003, I2 = 96.5%; SMD = 7.55, 95% CI: 3.92-11.18, P < 0.001, I2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 ( r = 0.16, 95% CI: 0.04-0.28, P = 0.009, I2 = 74.7%), neprilysin ( r = -0.47, 95% CI: -0.80-0.14, P = 0.005, I2 = 76.1%), and P-glycoprotein ( r = -0.31, 95% CI: -0.51-0.11, P = 0.002, I2 = 0.0%) in patients with Alzheimer's disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer's disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.012 | 0.037 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.015 | 0.013 |
| Bibliometrics | 0.010 | 0.011 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".