Integrating Plasma and Renal Biomarkers for Alzheimer’s Disease Diagnosis: A Systematic Review and Meta-Analysis of the Brain–Kidney Axis

Background Alzheimer’s disease (AD) represents a critical public health challenge requiring accessible, non-invasive biomarkers for early detection and disease monitoring. While cerebrospinal fluid (CSF) biomarkers remain the gold standard, their invasive nature limits widespread implementation. Emerging evidence suggests that systemic biomarkers—particularly those reflecting both neuronal injury and peripheral organ dysfunction—may provide complementary diagnostic value through the brain–kidney axis framework. Methods Following PRISMA 2020 guidelines, we systematically searched PubMed, Scopus, Web of Science, and Embase (2010–2025) for studies evaluating plasma and renal biomarkers in neurodegenerative diseases with primary focus on AD. We extracted data on biomarker concentrations, diagnostic accuracy metrics, and clinical correlations. Pooled standardized mean differences (SMDs) and area under the curve (AUC) values were calculated using random-effects meta-analysis. Study quality was assessed using the Newcastle–Ottawa Scale. Results Seventy-two studies encompassing 29,800 participants (15,420 cases; 14,380 controls) met inclusion criteria, with 42 studies (11,200 patients) specifically examining AD. Meta-analysis revealed significantly elevated plasma neurofilament light chain (NfL) in AD compared to controls (pooled SMD = 1.34, 95% CI: 1.05–1.63, p < 0.001, I² = 54%). Plasma cystatin C, a marker of renal function and amyloid clearance, demonstrated moderate elevation (pooled SMD = 0.89, 95% CI: 0.58–1.20, p < 0.001, I² = 48%). Combined biomarker panels integrating plasma and renal markers achieved superior diagnostic accuracy (four-biomarker panel AUC = 0.94; NfL + cystatin C + p-tau181 AUC = 0.91) compared to single biomarkers (NfL AUC = 0.78; cystatin C AUC = 0.71). Subgroup analyses demonstrated consistent findings across disease stages, geographic regions, and assay platforms. Publication bias assessment via funnel plots and Egger’s test showed no significant bias (p = 0.14 for NfL; p = 0.22 for cystatin C). Conclusions This systematic review and meta-analysis provide robust evidence that integrating plasma neuronal injury markers with renal function biomarkers enhances diagnostic accuracy for AD through the brain–kidney axis framework. The synergistic value of multi-organ biomarker panels reflects shared pathophysiological mechanisms including vascular dysfunction, impaired protein clearance, and systemic inflammation. These findings support the clinical translation of blood-based biomarker panels for AD screening, early detection, and disease monitoring, particularly in settings where CSF collection or neuroimaging are not feasible.