Plasma p-tau217/Aβ42 Ratio vs p-tau217 Alone in Alzheimer's Disease: A Systematic Review and Meta-Analysis
Background & Objective: Plasma phosphorylated tau 217 (p-tau217) is an incredibly accurate blood test for Alzheimer's disease (AD). While calculating the p-tau217/amyloid-β42 (Aβ42) ratio is thought to enhance precision, its true clinical advantage over p-tau217 alone remains debated. This systematic review and meta-analysis evaluates whether the plasma p-tau217/Aβ42 ratio actually improves our overall ability to detect AD pathology. Methodology: Following PRISMA guidelines, we searched PubMed, ClinicalTrials.gov, and the Cochrane Library. Studies were included if they directly compared the plasma p-tau217/Aβ42 ratio to p-tau217 alone, utilizing amyloid PET or cerebrospinal fluid biomarkers as the reference standard. The primary outcome was the reduction in intermediate (gray-zone) classifications. The secondary outcome was the mean difference (MD) in the area under the receiver operating characteristic curve (ΔAUC). Random-effects models were used to pool effect estimates using the R software. Results: Nine studies comprising ten cohorts met the inclusion criteria. Seven cohorts (n=2,052 unique patients) contributed to the gray-zone analysis, and nine perfectly matched cohorts (n=3,886 unique patients, following the exclusion of one study utilizing an inverted ratio) contributed to the ΔAUC analysis. Compared with p-tau217 alone, the p-tau217/Aβ42 ratio significantly reduced intermediate "gray-zone" classifications (RR=0.75, 95% CI 0.60–0.93; I²=42.3%), representing a 25% reduction in diagnostically ambiguous results. No significant difference in overall diagnostic discrimination (AUC) was observed between the ratio and p-tau217 alone (MD=0.00, 95% CI −0.01 to 0.02; I²=0.0%). Leave-one-out sensitivity analyses confirmed these findings were highly robust. Conclusion: The plasma p-tau217/Aβ42 ratio functions as an effective first-line screening tool that resolves ambiguous cases, significantly decreases gray-zone classifications, and increases diagnostic confidence. And it lowers the need for invasive confirmatory procedures, including lumbar punctures and costly PET scans. However, it does not significantly enhance absolute diagnostic discrimination (AUC) relative to p-tau217 alone. Key Words: p-tau217/Ab42 ratio, Alzheimer’s Disease.