Abstract
BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and cost-effective tools to detect amyloid pathology are urgently needed. Blood-based Tau phosphorylated at threonine 217 (pTau217) seems promising, but its reliability as a proxy for cerebrospinal fluid (CSF) status and ability to identify patients within the AD spectrum remain unclear. METHODS: We performed a systematic review and meta-analysis on the potential of blood pTau217 to differentiate amyloid-positive (A+) and amyloid-negative (A-) subjects. We included original studies reporting quantitative data on pTau217 concentrations in both blood and CSF in the AD continuum. The single-group meta-analysis computed the pooled pTau217 levels in blood and in CSF, separately in the A+ and A- groups, while the head-to-head meta-analysis compared the mean pTau217 concentrations in the A+ versus A- subjects, both in blood and CSF, stratifying by assessment method in both cases. RESULTS: Ten studies (819 A+; 1055 A-) were included. The mean pTau217 levels resulted higher in CSF than in blood and, crucially, in A+ individuals than in A- ones, regardless of the laboratory method employed. Most importantly, all laboratory techniques reliably distinguished A+ from A- subjects, whether applied to CSF or blood samples. CONCLUSIONS: These results confirm that blood-based pTau217 is a reliable marker of amyloid pathology with significant implications for clinical practice in the AD continuum. Indeed, pTau217 might be a non-invasive, scalable biomarker for early AD detection, reducing the reliance on more invasive, expansive, and less accessible methods. CLINICAL TRIAL REGISTRATION: Prospero CRD42024565187.