Differences Between Plasma and Cerebrospinal Fluid p-tau181 and p-tau231 in Early Alzheimer’s Disease

Abstract

Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer’s disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy—close to CSF p-tau231 and p-tau181—to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings.

Keywords

Alzheimer’s disease cerebrospinal fluid phosphorylated-tau plasma biomarkers

INTRODUCTION

The development of blood-based biomarkers for Alzheimer’s disease (AD) is pivotal for a rapid screening and diagnosis, as well as for tracking disease progression reducing the costs and burden of cerebrospinal fluid (CSF) and imaging assessments. Currently, the most promising blood biomarkers for detecting AD are amyloid-β (Aβ)_42/40 ratio, glial fibrillary acid protein, neurofibrillary light chain, and the newly identified different phosphorylated tau species [1 –3]. Despite the recent validation of these biomarkers in clinical cohorts of AD patients [4 –6], it is not yet well known how plasma p-tau species levels change in the very early stages of AD and across different neurodegenerative conditions. Furthermore, it is still controversial how different p-tau species in CSF and blood reflect the same pathological process and how they correlate with tau and amyloid AD markers. Thus, the first aim of the study was to compare the levels of p-tau181 and p-tau231 in plasma and CSF. The second objective of the work was to whether the levels of plasma differentiated early stages of AD patients from controls and patients with other neurodegenerative disorders. We hypothesized a significant increase in plasma p-tau181 and p-tau231 already in the early stages of AD, and a correlation with AD-related biomarkers such as CSF phosporylated and total tau and amyloid levels.

METHODS

Study population

This cross-sectional study included consecutive patients with mild cognitive impairment (MCI) or mild dementia who underwent CSF assessment at the Neurology Unit of Brescia and fulfilled a clinical diagnosis of AD according to NIA-AA criteria [7], prodromal or dementia with Lewy bodies (DLB) according to DLB consortium criteria [8, 9] or frontotemporal dementia (FTD) accoding to FTD consortium criteria [10]. All patients underwent routine blood analyses, magnetic resonance imaging (MRI), a standardized full cognitive and behavioral assessment, including the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) and an evaluation of basic and instrumental activities of daily living (ADL) [10]. The diagnosis of AD was carried out clinically and additionally confirmed biologically according to CSF biomarker profile (see next section). The following exclusion criteria were applied: 1) cognitive deficits or dementia not fulfilling clinical criteria for AD, DLB, or FTD; 2) prominent cortical or subcortical infarcts or brain/iron accumulation at imaging; 3) other neurologic disorders or medical conditions potentially associated with cognitive deficits; 4) bipolar disorder, schizophrenia, history of drug or alcohol abuse, or impulse control disorder; 5) recent traumatic events or acute fever/inflammation potentially influencing CSF and plasma biomarkers. For biomarkers comparison, a group of non-neurological controls (HC, n = 26) were included. This study was approved by the local ethics committee (NP 1471, DMA, Brescia) and was in conformity with the Helsinki Declaration; informed consent was obtained from all participants.

Fluid biomarkers

At enrollment, 3 milliliters of CSF from each participant were collected. Lumbar puncture was performed in fasting condition according to the standardized protocol of the outpatient clinic, from 09:00 to 11:00 in the morning, after clinical informed written consent was obtained. CSF was collected in sterile polypropylene tubes and gently mixed to avoid gradient effects. CSF was centrifugated and firstly processed for standard biochemical analyses, whereas two milliliters of CSF were stored in cryotubes at –80°C before biomarkers testing. Only patients with normal routine measures were included in further analyses. CSF concentrations were measured in duplicate by an ELISA test (Innotest tau antigen kit and Innotest Phospho-tau 181). Standard cut-off values for AD used by our laboratory are Aβ₄₂ < 650 ng/L, p-tau > 60 pg/mL, t-tau > 400 pg/mL and p-tau/ Aβ₄₂ ratio > 0.9. In the study, patients were classified according to clinical diagnosis, CSF Aβ₄₂ < 650 pg/mL and p-tau/ Aβ₄₂ ratio > 0.9 in AD and other neurodegenerative dementias (NDD) [12 –14]. Approximately 10 mL venous blood was collected in plastic tubes containing sodium ethylenediaminetetraacetic acid (EDTA) at the same day or within 6 months (n = 28) after CSF analyses. Blood samples were centrifuged at 2000 x g at 4°C for 8 min; plasma supernatant was collected, divided into aliquots, and frozen at –80°C until further use. CSF and plasma p-tau181 and p-tau231 were quantified by using Simoa® ptau-181 Advantage V2 Kit and Simoa® ptau-231 Advantage Kit through semi-automated SR-X Ultra-Sensitive Biomarker Detection System. The lower limit of quantification (LLOQ) as reported by manufacturer is 0.085 pg/mL for p-tau181 and 1.23 pg/ml for p-tau231. For plasma use of Simoa® ptau-231 Advantage Kit (assay used for CSF by manufacturer) we applied a 4-fold standard dilution and the same conditions applied for plasma p-tau181 application. Outliers were defined as subjects with values above more than 5 standard deviations of the mean of the group- separate analyses including and excluding outliers were performed.

Patient classification and statistical analysis

Data are presented as mean ± standard deviation for continuous variables and number (%) for categorical variables. Clinical and demographic characteristics as well as cognitive assessments and CSF and plasma p-tau181 and p-tau231 comparisons between diagnostic groups were performed using the Kruskal-Wallis, Bonferroni-corrected post-hoc analyses. The discriminative power in predicting AD CSF pattern was separately evaluated for CSF and plasma p-tau181 and p-tau231 using an overall accuracy analysis using the area under the curve (AUC) of a receiver operating characteristic curve (ROC). Correlations between CSF and plasma biomarkers were evaluated by non-parametric partial correlation analyses adjusted for the effect of age and sex; comparison between AUC ROC performance was evaluated using DeLong non parametric Method [15].

RESULTS

Participants’ characteristics and diagnosis according to AD CSF pattern

Ninety-one subjects, including 65 patients with cognitive impairment and 26 age-matched controls entered the study. The clinical assessment and CSF AD markers allowed the classification of patients in AD (n = 43, of which 22 MCI and 21 with mild dementia) and other neurodegenerative disorders (NDD n = 21, including 15 DLB and 6 FTD subjects). Table 1 shows biochemical and clinical characteristics of patients and controls. The groups did not differ in age or sex distribution, but in MMSE and CSF AD biomarker levels (Table 1).

Table 1

Clinical characteristics of study population.

	HC	NDD	MCI-AD	ADD	p
	(n = 26)	(n = 22)	(n = 22)	(n = 21)
Age, y	65.0±10.44	72.0±4.3	69.6±8.7	69.1±8.3	0.28
Disease duration, y	–	2.6±2.3	2.3±2.5	2.4±1.6	0.21
Gender, F % (n)	53% (14)	36% (8)	60% (26)	60% (26)	0.005
MMSE	29.3±1.2	25.5±4.2	26.1±1.7	20.7±1.8	< 0.001^abce
Education, y	10.2±5.2	10.6±4.4	8.4±4.1	7.1±2.4	0.87
CSF markers
t-tau, pg/mL	250.6±89.6	364.7±163.5	644.4±344.1	699.3±350.1	< 0.001^abcd
p-tau181IT, pg/mL	32.1±8.9	44.8±17.5	90.1±34.1	133.5±81.7	< 0.001^abcd
Aβ₄₂, pg/mL	1142±286	1269.4±545.3	527.0±159.7	540.4±126.6	< 0.001^abcd
p-tau/ Aβ₄₂ ratio	0.28±0.03	0.42±0.15	1.77±0.56	2.7±2.3	< 0.001^abcd
CSF p-tau markers
p-tau181, pg/mL	15.7±13.5	28.8±21.5	80.5±57.0	108.5±99.6	< 0.001^abcd
p-tau231, pg/mL	30.1±36.1	66.1±66.2	142.2±67.7	262.0±230.1	< 0.001^abcd
Plasma p-tau biomarkers
p-tau181, pg/mL	1.91±1.06	1.9±0.95	3.8±1.33	3.6±1.8	< 0.001^abcd
p-tau231, pg/mL	2.1±1.19	3.0±1.72	4.6±2.04	5.4±2.02	< 0.001^abcd

Aβ₄₂, amyloid beta 1–42; ADD, Alzheimer’s disease with dementia; HC, healthy controls; MCI- AD, mild cognitive impairment due to Alzheimer’s disease; MMSE, Mini-Mental state Examination; mL, milliliters; NDD, non-Alzheimer neurodegenerative disorders; p-tau181IT, p-tau 181 isoform tested by Innotest assay; pg, picograms. ^asignificant comparison HC versus MCI-AD; ^bsignificant comparison HC versus ADD; ^csignificant comparison NDD versus MCI-AD; ^dsignificant comparison NDD versus ADD; ^esignificant comparison HC versus NDD

Plasma/CSF biomarkers levels

Plasma and CSF p-tau181 and p-tau231 levels were significantly higher in either MCI-AD or ADD and differentiated both MCI-AD and ADD from HC and NDD (p < 0.001 for all post-hoc analyses, Table 1 and Fig. 1). Five outliers were identified; they included one case (ADD) for CSF-ptau181, one subject (NDD) for plasma p-tau181, two subjects (NDD n = 1 and ADD n = 1) and one case (MCI-AD) for plasma-tau231. No differences in p-tau181 or p-tau231 CSF levels between MCI-AD and ADD were observed. No correlation was found between age and sex and both CSF and plasma p-tau181 and p-tau231 levels.

Fig. 1

Differences in CSF and plasma p-tau181, p-tau231 levels according to each groups. ADD, Alzheimer’s disease with dementia; HC, healthy controls; MCI-AD, mild cognitive impairment associated with AD pathology; NDD, non-Alzheimer neurodegenerative disorders.

Discriminant analyses for CSF and plasma biomarkers

We investigated how plasma and CSF p-tau181 and p-tau231 levels discriminate AD using ROC analysis. Plasma p-tau181 and p-tau231 accurately discriminated AD from non-AD individuals, with an AUC of 0.79 (CI95% 0.69–0.90%) and 0.87 (CI95% 0.79–0.95%), respectively. Innotest Standard p-tau CSF levels exhibited an AUC of 0.94 (CI95% 0.88–0.98%) in discriminating alone the AD pattern. The direct comparison between AUC-ROC curves indicated a significant difference between Innotest p-tau and plasma p-tau1818 (p = 0.0034, difference between areas 0.14), whereas p-tau231 exhibited a similar performance compared to Innotest p-tau (p = 0.11, difference between areas 0.07) (Supplementary Figure 1). Thus, p-tau181 sensitivity was 78% and specificity 80% using the best cutoff (2.67 pg/mL); for-p-tau231 sensitivity was 80%, specificity 83% using the best cutoff 3.50 pg/mL. Similarly, CSF p-tau181 and p-tau231 had an AUC of 0.89 (95% CI 0.82–0.96%) and 0.91 (CI 95% 0.84–0.97%), respectively with no differences compared to Innotest p-tau performance (AUC 0.94, CI 95% 0.88–0.98) (Supplementary Figure 1). Using p-tau181 best cutoffs 34% of AD and 19% of non-AD were misclassified. For p-tau231 25% of AD and 17% of non-AD patients were misclassified. When using CSF p-tau INNOTEST only (not using the p-tau/Aβ₄₂ ratio) 20% of AD and 9% of non-AD were misclassified.

Correlations between plasma and CSF biomarkers

Plasma p-tau181 levels exhibited a strong correlation with CSF levels (r = 0.47, p < 0.001). A similar correlation was observed between plasma and CSF p-tau231 (r = 0.49, p < 0.001). p-tau181 and p-tau231 levels strongly correlated either in CSF (r = 0.73, p = 0.001) or plasma (r = 0.56, p < 0.001).

Plasma p-tau181 and p-tau231 exhibited significant positive correlation with CSF Innotest p-tau (r = 0.36, p = 0.006 and r = 0.45, p < 0.001), p-tau/ Aβ₄₂ ratio (r = 0.47, p < 0.001 and r = 0.55, p < 0.001) and exhibited a negative correlation with Aβ₄₂ levels (r = –0.38, p = 0.004 and r = –0.37, p = 0.004) (Fig. 2).

Fig. 2

Non-parametric partial correlations between CSF and plasma biomarkers in the sample. Blue indicates positive correlation, red indicates negative correlations, white indicates no significant correlations. Aβ₄₂, amyloid-β 1–42; CSF, cerebrospinal fluid; PL, plasma.

CSF p-tau181 and p-tau231 levels correlated positively with CSF t-tau (r = 0.54, p = 0.001; r = 0.57, p = 0.001), Innotest p-tau (r = 0.72, p = 0.001; r = 0.69, p = 0.001) and p-tau/Aβ₄₂ ratio (r = 0.67, p = 0.001; r = 0.66, p = 0.001) and negatively with Aβ₄₂ (r = –0.32, p = 0.015; r = –0.33, p = 0.011 respectively) (Fig. 2).

DISCUSSION

In this study, plasma p-tau181 and plasma p-tau231 levels were significantly increased in early AD and mirrored CSF p-tau181 and p-tau231 levels. Further, there was a strong correlation between plasma and CSF levels of p-tau181 and ptau231 with AD-related biomarkers including total tau, and Aβ₄₂. Both plasma and CSF levels of p-tau181 and p-tau 231 shared high diagnostic accuracy for discriminate AD subjects from non-AD individuals. The results are important for supporting the use of plasma biomarkers in both clinical and research scenarios.

These findings extend previous studies addressing blood-based biomarkers such as phosphorylated tau in independent cohorts [15 –19]. Previous reports were particularly consistent for plasma p-tau181, as its levels are increased in AD [1 , 20–24]. Very recently, Ashton and colleagues additionally identified plasma p-tau231 as a new potential marker of AD pathology claiming that it might be especially useful for the early phases of the disease [2].

In this study carried out on a series of subjects who underwent CSF analysis of AD-related biomarkers for diagnostic purposes [7], we have found that both p-tau181 and p-tau231 in plasma and CSF were closely related in early stages of AD. Findings showed a strong correlation between the two different phosphorylated species p-tau181 and p-tau231 both in CSF and in plasma and a significant increase of both biomarkers in MCI-AD and ADD patients [1 , 22]. The diagnostic performances of plasma p-tau181 and p-tau231 were very high and very close to the performance of CSF assays, as confirmed by direct comparison of diagnostic performances. In fact, the present findings argue for the great potential of both p-tau181 and p-tau231 as highly sensitive markers of AD pathology already in the MCI stages of the disease. Furthermore, the strong correlations observed for p-tau181 and p-tau231 with CSF AD markers strongly support their use as promising proxies for tracking disease progression over time, for predicting amyloid burden in preclinical and prodromal AD as well as for evaluating the effect of anti-amyloid therapies. In fact, the recent advances in pharmacological and non-pharmacological strategies for the treatment of AD requires a rapid change in the way the specialists are able to detect and follow AD patients [4 –6].

The major limitation of the study resides in the sample size of both AD patients and non-AD patients thus requiring further larger validations with longitudinal progression to better define the diagnostic accuracy and ideal cut-offs [1 , 13]. The data, however, are highly consistent with published larger series and demonstrated the high performance and consistency between CSF and plasma levels, even including cases with frozen biosamples evaluated during a time span of several months. The number of outliers was indeed relatively low in CSF and plasma, underlying the usefulness of methods even in large and less characterised samples such as screening tool. Further studies are still needed in order to evaluate the role of preanalytical or clinical confounders for disentangling cases with borderline or discordant p-tau values. A direct comparison with other plasma markers including p-tau217, Aβ_42/40, and glial fibrillary acid protein will be also pivotal in order to evaluate the best biomarker combination both for diagnostic and prognostic purposes. The number of miss-classified cases using plasma biomarker is indeed still relevant, as it includes between a fifth and a third of subjects. This might suggest that the combination of different p-tau species (namely 181, 231, but also p-tau 217) might increase the diagnostic performance of the assays for large population screening or for subjects with borderline values. The combination with sensitive neuronal damage markers such as neurofibrillary light chain need also to be challenged in larger groups for increasing the validity of single or cobned use of p-tau species. Further studies are also definitively needed to disentangle the complex mechanisms leading to the release of different p-tau species- as they might define different subtypes of patients or specific phases of the neurodegenereative processes.

In conclusion, this study showed that the assessment of plasma p-tau 181 and p-tau231 ls a valuable method for early diagnosis of AD closely mirroring the discriminative accuracy of CSF p-tau 181 and p-tau231 markers.

In this framework, plasma biomarkers represent a unique opportunity for clinicians, pharma industries and healthcare systems to reduce the costs and burden of assessment, improve the ability to diagnose and track the disease progression in the new AD era.

Footnotes

ACKNOWLEDGMENTS

The authors thank the patients who participated to the study and the health personnel involved in the clinical assistance and care of patients. This study is supported by the Airalzh-AGYR2020 grant issued to A.B. The authors acknowledge the contribution of Fondazione A. Nocivelli.

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

References

Karikari

, Pascoal

, Ashton

, Janelidze

, Benedet

, Rodriguez

, Chamoun

, Savard

, Kang

, Therriault

, Scholl

, Massarweh

, Soucy

, Hoglund

, Brinkmalm

, Mattsson

, Palmqvist

, Gauthier

, Stomrud

, Zetterberg

, Hansson

, Rosa-Neto

, Blennow

(2020) Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: A diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol 19, 422–433.

Ashton

, Pascoal

, Karikari

, Benedet

, Lantero-Rodriguez

, Brinkmalm

, Snellman

, Scholl

, Troakes

, Hye

, Gauthier

, Vanmechelen

, Zetterberg

, Rosa-Neto

, Blennow

(2021) Plasma p-tau231: A new biomarker for incipient Alzheimer’s disease pathology. Acta Neuropathol 141, 709–724.

Mielke

, Frank

, Dage

, Jeromin

, Ashton

, Blennow

, Karikari

, Vanmechelen

, Zetterberg

, Algeciras-Schimnich

, Knopman

, Lowe

, Bu

, Vemuri

, Graff-Radford

, Jack

Jr. , Petersen

(2021) Comparison of plasma phosphorylated tau species with amyloid and tau positron emission tomography, neurodegeneration, vascular pathology, and cognitive outcomes. JAMA Neurol 78, 1108–1117.

Alawode

DOT

, Heslegrave

, Ashton

, Karikari

, Simren

, Montoliu-Gaya

, Pannee

, A

, Weston

PSJ

, Lantero-Rodriguez

, Keshavan

, Snellman

, Gobom

, Paterson

, Schott

, Blennow

, Fox

, Zetterberg

(2021) Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer’s disease. J Intern Med 290, 583–601.

Zetterberg

, Blennow

(2021) Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener 16, 10.

Leuzy

, Cullen

, Mattsson-Carlgren

, Hansson

(2021) Current advances in plasma and cerebrospinal fluid biomarkers in Alzheimer’s disease. Curr Opin Neurol 34, 266–274.

Jack

Jr. , Bennett

, Blennow

, Carrillo

, Dunn

, Haeberlein

, Holtzman

, Jagust

, Jessen

, Karlawish

, Liu

, Molinuevo

, Montine

, Phelps

, Rankin

, Rowe

, Scheltens

, Siemers

, Snyder

, Sperling

, Contributors (2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14, 535–562.

McKeith

, Boeve

, Dickson

, Halliday

, Taylor

, Weintraub

, Aarsland

, Galvin

, Attems

, Ballard

, Bayston

, Beach

, Blanc

, Bohnen

, Bonanni

, Bras

, Brundin

, Burn

, Chen-Plotkin

, Duda

, El-Agnaf

, Feldman

, Ferman

, Ffytche

, Fujishiro

, Galasko

, Goldman

, Gomperts

, Graff-Radford

, Honig

, Iranzo

, Kantarci

, Kaufer

, Kukull

, Lee

VMY

, Leverenz

, Lewis

, Lippa

, Lunde

, Masellis

, Masliah

, McLean

, Mollenhauer

, Montine

, Moreno

, Mori

, Murray

, O’Brien

, Orimo

, Postuma

, Ramaswamy

, Ross

, Salmon

, Singleton

, Taylor

, Thomas

, Tiraboschi

, Toledo

, Trojanowski

, Tsuang

, Walker

, Yamada

, Kosaka

(2017) Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89, 88–100.

McKeith

, Ferman

, Thomas

, Blanc

, Boeve

, Fujishiro

, Kantarci

, Muscio

, O’Brien

, Postuma

, Aarsland

, Ballard

, Bonanni

, Donaghy

, Emre

, Galvin

, Galasko

, Goldman

, Gomperts

, Honig

, Ikeda

, Leverenz

, Lewis

SJG

, Marder

, Masellis

, Salmon

, Taylor

, Tsuang

, Walker

, Tiraboschi

, prodromal DLB Diagnostic Study Group (2020) Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94, 743–755.

10.

Rascovsky

, Hodges

, Knopman

, Mendez

, Kramer

, Neuhaus

, van Swieten

, Seelaar

, Dopper

, Onyike

, Hillis

, Josephs

, Boeve

, Kertesz

, Seeley

, Rankin

, Johnson

, Gorno-Tempini

, Rosen

, Prioleau-Latham

, Lee

, Kipps

, Lillo

, Piguet

, Rohrer

, Rossor

, Warren

, Fox

, Galasko

, Salmon

, Black

, Mesulam

, Weintraub

, Dickerson

, Diehl-Schmid

, Pasquier

, Deramecourt

, Lebert

, Pijnenburg

, Chow

, Manes

, Grafman

, Cappa

, Freedman

, Grossman

, Miller

(2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134, 2456–2477.

11.

Pilotto

, Imarisio

, Carrarini

, Russo

, Masciocchi

, Gipponi

, Cottini

, Aarsland

, Zetterberg

, Ashton

, Hye

, Bonanni

, Padovani

(2021) Plasma neurofilament light chain predicts cognitive progression in prodromal and clinical dementia with Lewy bodies. J Alzheimers Dis 82, 913–919.

12.

Campbell

, Ashrafzadeh-Kian

, Petersen

, Mielke

, Syrjanen

, van Harten

, Lowe

, Jack

Jr. , Bornhorst

, Algeciras-Schimnich

(2021) P-tau/Abeta42 and Abeta42/40 ratios in CSF are equally predictive of amyloid PET status. Alzheimers Dement (Amst) 13, e12190.

13.

Padovani

, Premi

, Pilotto

, Gazzina

, Cosseddu

, Archetti

, Cancelli

, Paghera

, Borroni

(2013) Overlap between frontotemporal dementia and Alzheimer’s disease: Cerebrospinal fluid pattern and neuroimaging study. J Alzheimers Dis 36, 49–55.

14.

Borroni

, Premi

, Agosti

, Alberici

, Cerini

, Archetti

, Lanari

, Paghera

, Lucchini

, Caimi

, Padovani

(2011) CSF Alzheimer’s disease-like pattern in corticobasal syndrome: Evidence for a distinct disorder. J Neurol Neurosurg Psychiatry 82, 834–838.

15.

DeLong

, DeLong

, Clarke-Pearson

(1988) . Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach. Biometrics 44, 837–845.

16.

Janelidze

, Mattsson

, Palmqvist

, Smith

, Beach

, Serrano

, Chai

, Proctor

, Eichenlaub

, Zetterberg

, Blennow

, Reiman

, Stomrud

, Dage

, Hansson

(2020) Plasma P-tau181 in Alzheimer’s disease: Relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med 26, 379–386.

17.

Thijssen

, La Joie

, Wolf

, Strom

, Wang

, Iaccarino

, Bourakova

, Cobigo

, Heuer

, Spina

, VandeVrede

, Chai

, Proctor

, Airey

, Shcherbinin

, Duggan Evans

, Sims

, Zetterberg

, Blennow

, Karydas

, Teunissen

, Kramer

, Grinberg

, Seeley

, Rosen

, Boeve

, Miller

, Rabinovici

, Dage

, Rojas

, Boxer

, Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators (2020) Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med 26, 387–397.

18.

Cullen

, Zetterberg

, Insel

, Olsson

, Andreasson

, Alzheimer’s Disease Neuroimaging Initiative, Blennow

, Hansson

, Mattsson-Carlgren

(2020) Comparing progression biomarkers in clinical trials of early Alzheimer’s disease. Ann Clin Transl Neurol 7, 1661–1673.

19.

Suarez-Calvet

, Karikari

, Ashton

, Lantero Rodriguez

, Mila-Aloma

, Gispert

, Salvado

, Minguillon

, Fauria

, Shekari

, Grau-Rivera

, Arenaza-Urquijo

, Sala-Vila

, Sanchez-Benavides

, Gonzalez-de-Echavarri

, Kollmorgen

, Stoops

, Vanmechelen

, Zetterberg

, Blennow

, Molinuevo

, Study A (2020) Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Abeta pathology are detected. EMBO Mol Med 12, e12921.

20.

Hansson

(2021) Biomarkers for neurodegenerative diseases. Nat Med 27, 954–963.

21.

O’Connor

, Karikari

, Poole

, Ashton

, Lantero Rodriguez

, Khatun

, Swift

, Heslegrave

, Abel

, Chung

, Weston

PSJ

, Pavisic

, Ryan

, Barker

, Rossor

, Polke

, Frost

, Mead

, Blennow

, Zetterberg

, Fox

(2021) Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: A longitudinal cohort study. Mol Psychiatry 26, 5967–5976.

22.

Pereira

, Janelidze

, Stomrud

, Palmqvist

, van Westen

, Dage

, Mattsson-Carlgren

, Hansson

(2021) Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain 144, 2826–2836.

23.

Therriault

, Benedet

, Pascoal

, Lussier

, Tissot

, Karikari

, Ashton

, Chamoun

, Bezgin

, Mathotaarachchi

, Gauthier

, Saha-Chaudhuri

, Zetterberg

, Blennow

, Rosa-Neto

, Alzheimer’s Disease Neuroimaging Initiative (2021) Association of plasma P-tau181 with memory decline in non-demented adults. Brain Commun 3, fcab136.

24.

Mielke

, Hagen

, Xu

, Chai

, Vemuri

, Lowe

, Airey

, Knopman

, Roberts

, Machulda

, Jack

Jr. , Petersen

, Dage

(2018) Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement 14, 989–997.

25.

Karikari

, Benedet

, Ashton

, Lantero Rodriguez

, Snellman

, Suarez-Calvet

, Saha-Chaudhuri

, Lussier

, Kvartsberg

, Rial

, Pascoal

, Andreasson

, Scholl

, Weiner

, Rosa-Neto

, Trojanowski

, Shaw

, Blennow

, Zetterberg

, Alzheimer’s Disease Neuroimaging Initiative (2021) Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry 26, 429–442.

26.

Ashton

, Janelidze

, Al Khleifat

, Leuzy

, van der Ende

, Karikari

, Benedet

, Pascoal

, Lleo

, Parnetti

, Galimberti

, Bonanni

, Pilotto

, Padovani

, Lycke

, Novakova

, Axelsson

, Velayudhan

, Rabinovici

, Miller

, Pariante

, Nikkheslat

, Resnick

, Thambisetty

, Scholl

, Fernandez-Eulate

, Gil-Bea

, Lopez de Munain

, Al-Chalabi

, Rosa-Neto

, Strydom

, Svenningsson

, Stomrud

, Santillo

, Aarsland

, van Swieten

, Palmqvist

, Zetterberg

, Blennow

, Hye

, Hansson

(2021) A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun 12, 3400.