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Systematic review of amyloid-beta clearance
proteins from the brain to the periphery: implications
for Alzheimer’s disease diagnosis and therapeutic
targets
Letian Huang, Mingyue Liu, Ze Li, Bing Li, Jiahe Wang, Ke Zhang
2025, 20 (12):
3574-3590.
doi: 10.4103/NRR.NRR-D-24-00865
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, I
2
= 78.4%; SMD = 1.24, 95% CI:
0.01–2.48, P = 0.048, I
2
= 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35–1.66,
P = 0.003, I
2
= 96.5%; SMD = 7.55, 95% CI: 3.92–11.18, P < 0.001, I
2
= 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, I
2
= 74.7%), neprilysin (r = –0.47, 95%
CI: –0.80–0.14, P = 0.005, I
2
= 76.1%), and P-glycoprotein (r = –0.31, 95% CI: –0.51–0.11,
P = 0.002, I
2
= 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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