CSF tau phosphorylation at T217 and T205 are improved biomarkers of amyloid and tau pathology in Alzheimer disease

Abstract

CSF Aβ42/Aβ40 and tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer disease (AD). This study used mass spectrometry to measure concentrations of 9 phosphorylated and 5 non-phosphorylated species, and phosphorylation occupancies (phosphorylated/non-phosphorylated [%]) at 10 sites. In 750 individuals with a median age of 71.2 years, CSF pT217/T217 (%) predicted amyloid PET status slightly better than Aβ42/Aβ40 (p=0.02). In amyloid PET positive individuals (n=263), CSF pT217/T217 (%) was more strongly correlated with amyloid PET Centiloid (Spearman ρ=0.69) than Aβ42/Aβ40 (ρ = -0.42, p<0.0001). CSF pT217/T217 (%) and pT205/T205 (%) were superior to Aβ42/Aβ40 and similar to tau PET in prediction of cognitive impairment. In two independent cohorts with symptomatic AD (n=55 and n=90), CSF pT217/T217 (%) and pT205/205 (%) were better correlated with tau PET measures than CSF p-tau181 concentration. CSF pT217/T217 (%) and pT205/205 (%) represent improved CSF biomarkers of amyloid and tau pathology in AD.

Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease

“…The phosphorylation occupancy represents the percentage of tau phosphorylated at a certain amino acid position, which is a more specific measure of phosphorylation not confounded with total tau concentrations, and superior to the corresponding p-tau concentration in prediction of abnormal amyloid status. 34,35 Briefly, 25 μl of the master mix solution containing detergent and chaotropic reagents (final 1% NP-40, 5 mM guanidine, protease inhibitor cocktail [Roche]) and 2.5 ng of internal standards for tau ( 15 N isotope-labeled 2N4R tau [gift from Dr. Guy Lippens]) were added to 0.5 ml of CSF in polypropylene tubes.…”

“…Guy Lippens]) were added to 0.5 ml of CSF in polypropylene tubes. Tau and p-tau species from N-terminal and Mid-domain were extracted by IP using incubation under rotation at room temperature during 2 hours with 30 μl of sepharose beads cross-linked to HJ8.5 and Tau1 anti-tau antibodies with epitopes residing in N-terminal (27)(28)(29)(30)(31)(32)(33)(34)(35) and mid-domain (192-199) of tau, respectively (see Fig 1). The post-IP CSF samples were collected in new polypropylene tubes and stored at À80 C until the MTBR-tau analysis.…”

“…For p‐tau measures, the phosphorylation occupancies at different tau residues (pT111/T111, pT153/T153, pT181/T181, pS199/S199, pS202/S202, pT205/T205, pT217/T217, and pT231/T231) were reported. The phosphorylation occupancy represents the percentage of tau phosphorylated at a certain amino acid position, which is a more specific measure of phosphorylation not confounded with total tau concentrations, and superior to the corresponding p‐tau concentration in prediction of abnormal amyloid status 34,35 . Briefly, 25 μl of the master mix solution containing detergent and chaotropic reagents (final 1% NP‐40, 5 mM guanidine, protease inhibitor cocktail [Roche]) and 2.5 ng of internal standards for tau ( 15 N isotope‐labeled 2N4R tau [gift from Dr.…”

Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

“…After 5 days of treatment, the AD neurons were checked for their expression levels of phosphorylated tau (pTau181, pTau205). Phosphorylated-tau181 (pTau181) is an early biomarker of AD pathology and correlates well with cognitive declines [40] while, in contrast, Phosphorylated-tau205 (pTau205) and total tau levels increase at later stages of disease progression [41]. To investigate whether sildenafil reduces pTau accumulation in AD neurons, cells were lysed, Fig.…”

The Association of Alzheimer’s Disease-related Blood-based Biomarkers with Cognitive Screening Test Performance in the Congolese Population in Kinshasa

“…As such, the Aβ42/40 ratio is a better predictor of the presence of brain amyloid plaques than the plasma concentrations alone. 13,14,15 Low CSF and plasma Aβ42/40 ratios and high tau concentrations are fluid biomarkers for AD pathology 13 Although obtaining the biomarkers via CSF has been customary practice, obtaining the biomarkers from blood is more accessible than CSF and is preferable for both screening and sampling purposes. 13 While there are several caveats making blood more challenging than CSF for brain biomarkers, such as dilution with other plasma proteins and degradation by proteases in the blood, novel developments in ultrasensitive immunoassays as well as mass spectrometry bring promising results for the use of blood biomarkers over CSF biomarkers.…”