Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders

Abstract

IMPORTANCEThere are limitations in current diagnostic testing approaches for Alzheimer disease (AD).OBJECTIVE To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD.DESIGN, SETTING, AND PARTICIPANTS Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017).EXPOSURES Plasma P-tau217. MAIN OUTCOMES AND MEASURES Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]).RESULTS Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22).CONCLUSIONS AND RELEVANCE Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma-and MRI-based biomarkers, and its performance wa...

Diagnostic value of plasma neurofilament light: A multicentre validation study

“…Our < 65-year plasma NfL cut-offs (19.4 pg/mL, 21.5 pg/mL, 30.0 pg/mL) were substantially lower as to compared older cut-offs (38.0 pg/mL, 46.0 pg/mL, 54.8 pg/mL) and when this was applied, EOAD patients had the equivalent rate of abnormal plasma NfL as typical AD dementia -consistent with the reported literature on familial AD 56,57 . We also observed that age-related cut-offs may be more sensitive to neurodegeneration related to Aβ deposition, although it is clear that recent developments in plasma p-tau181 or p-tau217 would be a superior measure of Aβ and tau pathologies 10,11,14,15,51,58 . In individuals < 65 years, rates of abnormal plasma NfL were 3-fold higher in Aβ + controls as compared to Aβ-controls and also higher in MCI Aβ + than MCI Aβ-.…”

“…Recent advances in ultrasensitive immunological assays [10][11][12][13][14][15] and immunoprecipitation mass spectrometry (IPMS) methods [16][17][18] have been developed to measure neurodegenerative biomarkers in blood. NfL can be quanti ed at femtomolar concentrations in plasma or serum, which has enabled the reliable detection of NfL not only in symptomatic patients but also in cognitively unimpaired (CU) individuals of all ages 19 .…”

The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice

“…PET ligands speci c for NFTs in the AD brain recently have been developed, yet limitations including high costs, need for specialized instrumentation, and lack of binding to different tau strains (77,78) suggests that uid biomarkers, especially those obtained by minimally invasive procedures, such as a blood test, may be complementary or even advantageous to imaging biomarkers. A recent example is plasma pT217-tau, which recently has been shown to distinguish AD from other neurodegenerative diseases with high sensitivity and speci city (79,80). Here, we used neuronal exosomes enriched from the serum to test total tau concentration as an outcome measure for the treatment.…”

Soluble P-tau217 reflects both amyloid and tau pathology in the human brain and mediates the association of amyloid with neocortical tau

“…Study participants were from two cohorts. First, we included subjects from a biomarker-neuropathology cohort study (the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program), also described previously 6 . Second, we included subjects from the prospective cohort study BioFINDER-2 (clinical trials: NCT03174938), explained previously 6 .…”

“…Recently, it has been shown that plasma levels of hyperphosphorylated tau (including both P-tau181 4,5 and P-tau217 6 ) are markedly elevated in patients with AD. Plasma P-tau217 levels have particularly high accuracy for AD, and are correlated with tangle densities in post-mortem data 6 . However, recent studies have suggested that CSF P-tau217 (and other P-tau variants) can be increased as a function of Aβ accumulation, in individuals who are tau negative as determined by positron emission tomography (PET) 7,8 (but note that tau PET has limited sensitivity to detect very sparse tau aggregation 9 ).…”