Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials.

Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials. Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.

Ossenkoppele R ，van der Kant R ，Hansson O 《-》

Time course of phosphorylated-tau181 in blood across the Alzheimer's disease spectrum.

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

Moscoso A ，Grothe MJ ，Ashton NJ ，Karikari TK ，Rodriguez JL ，Snellman A ，Suárez-Calvet M ，Zetterberg H ，Blennow K ，Schöll M ，Alzheimer’s Disease Neuroimaging Initiative ... -  《-》

Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.

Ashton NJ ，Pascoal TA ，Karikari TK ，Benedet AL ，Lantero-Rodriguez J ，Brinkmalm G ，Snellman A ，Schöll M ，Troakes C ，Hye A ，Gauthier S ，Vanmechelen E ，Zetterberg H ，Rosa-Neto P ，Blennow K ... -  《-》

Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.

CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%). Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

Karikari TK ，Pascoal TA ，Ashton NJ ，Janelidze S ，Benedet AL ，Rodriguez JL ，Chamoun M ，Savard M ，Kang MS ，Therriault J ，Schöll M ，Massarweh G ，Soucy JP ，Höglund K ，Brinkmalm G ，Mattsson N ，Palmqvist S ，Gauthier S ，Stomrud E ，Zetterberg H ，Hansson O ，Rosa-Neto P ，Blennow K ... -  《-》

Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer's Disease.

Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain. NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline. We demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R2), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (βstd = 0.16) and impaired (βstd = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2 = 0.20). Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal.

Lantero-Rodriguez J ，Salvadó G ，Snellman A ，Montoliu-Gaya L ，Brum WS ，Benedet AL ，Mattsson-Carlgren N ，Tideman P ，Janelidze S ，Palmqvist S ，Stomrud E ，Ashton NJ ，Zetterberg H ，Blennow K ，Hansson O ... -  《Molecular Neurodegeneration》