CSF tau phosphorylation at sites 217 and 205 mediate the relationship between PET amyloid and downstream AD markers

Abstract Background Associations between amyloid and downstream measures of Alzheimer disease (AD) are often lacking. In autosomal dominant AD (ADAD), cerebrospinal fluid (CSF) phosphorylated tau 217 and 181 (pT217 and pT181) increase shortly after amyloid positron emission tomography (PET), followed by tau 205 (pT205), then tau PET. Each site also tracks closely with disease progression and is associated with longitudinal cognitive decline. Collectively these findings lead to the question of which p‐tau sites affect the relationship between amyloid and downstream AD markers (i.e., tau, MRI cortical thickness, Clinical Dementia Rating [CDR] Scale status), and more specifically whether they mediate such associations. Method CSF tau phosphorylation occupancy on 217, 181 and 205 residues, CSF total tau (t‐tau), amyloid PET, ADAD cortical thickness signature, and CDR status were measured in 150 individuals from the Dominantly Inherited Alzheimer Network (non‐mutation carrier [MC‐]; n=64; and mutation carrier [MC+]; n=86). Three multiple mediation analyses assuming nonlinear relationships were performed with amyloid PET as the predictor variable, CSF p‐tau sites (pT217, pT181, pT205) and t‐tau (when appropriate) as mediators, and either CSF t‐tau, cortical thickness, or CDR status as the outcome variables. For each model, estimated years to symptom onset (EYO), age, sex, and ADAD mutation status were included as covariates. All models were run with 500 iterations to bootstrap confidence intervals. Result Increased amyloid PET was associated with elevated CSF pT217, pT181, and pT205 ( p ’s<0.03). For each model, the effects of amyloid PET on downstream AD markers were jointly mediated by CSF pT217 and pT205. Specifically, elevated CSF pT217 and pT205 were associated with increased CSF t‐tau, decreased cortical thickness, and higher CDR scores ( p ’s<0.01). CSF t‐tau and pT181 did not mediate these relationships ( p ’s>0.05). Conclusion Elevated pT217 and pT205, but not pT181 or t‐tau, mediate the relationship between amyloid and downstream AD biomarkers in ADAD. AD‐related brain atrophy and clinical status may be dependent on specific tau sites; future mechanistic experiments are needed to fully understand such relationships. These results support the hypothesis that tau phosphorylation at specific sites plays a critical role in the progression and pathogenesis of ADAD, and may be a possible target for future treatments.