MRI-derived periventricular diffusivity contextualizes plasma pTau217 associations with Alzheimer pathology: a discovery–validation study

Background Plasma phosphorylated tau 217 (pTau217) is a promising scalable marker of Alzheimer pathology, but discordance with positron emission tomography (PET) limits context-free interpretation. We tested whether magnetic resonance imaging (MRI)-derived periventricular diffusivity (PVeD) modifies associations between pTau217 and Alzheimer pathology. Methods In this observational discovery–validation study, standardized pTau217 × PVeD interactions were tested for amyloid PET, tau PET, structural and vascular MRI, and cognitive outcomes in 602 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 2,313 participants from the Health and Aging Brain Study–Health Disparities (HABS-HD). Analyses were adjusted for prespecified covariates and false discovery rate correction. Results In ADNI, pTau217 associations with amyloid Centiloid (interaction β = −0.096, 95% confidence interval [CI] − 0.154 to − 0.037; adjusted P = .018) and meta-temporal tau PET (β = −0.092, 95% CI − 0.158 to − 0.027; adjusted P = .018) were stronger at lower PVeD. Among participants with high pTau217, low PVeD was associated with faster cognitive decline than high PVeD (difference = − 0.100 Preclinical Alzheimer Cognitive Composite [PACC] units/year, 95% CI − 0.161 to − 0.038; adjusted P = .002). HABS-HD replicated the amyloid interaction (β = −0.109, 95% CI − 0.147 to − 0.070; adjusted P < .001) and multiple tau PET interactions; the high-pTau217/low-PVeD profile also declined faster (difference = − 0.037 PACC units/year; adjusted P = .002). Conclusions PVeD reproducibly contextualized associations between plasma pTau217 and PET-defined Alzheimer pathology across cohorts with different participant composition, pTau217 assays, PET tracers, and cognitive measures. The findings motivate prospective evaluation of MRI-informed interpretation of blood biomarkers, but PVeD is an indirect diffusion marker and the observational design does not establish mechanism, clinical utility, or decision thresholds.