. 2022 Nov 12;14(1):172.

doi: 10.1186/s13195-022-01116-2.

Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease

Edward N Wilson^{1

2}, Christina B Young³, Javier Ramos Benitez³, Michelle S Swarovski³, Igor Feinstein⁴, Manu Vandijck⁵, Yann Le Guen³, Nandita M Kasireddy³, Marian Shahid³, Nicole K Corso³, Qian Wang³, Gabriel Kennedy³, Alexandra N Trelle⁶, Betty Lind^{7

8}, Divya Channappa^{3

9}, Malia Belnap³, Veronica Ramirez³, Irina Skylar-Scott³, Kyan Younes³, Maya V Yutsis³, Nathalie Le Bastard⁵, Joseph F Quinn^{7

8}, Christopher H van Dyck¹⁰, Angus Nairn¹⁰, Carolyn A Fredericks³, Lu Tian¹¹, Geoffrey A Kerchner³, Thomas J Montine⁹, Sharon J Sha³, Guido Davidzon¹², Victor W Henderson^{3

13

14}, Frank M Longo^{3

13}, Michael D Greicius^{3

13}, Anthony D Wagner^{13

6}, Tony Wyss-Coray^{3

13}, Kathleen L Poston^{3

13}, Elizabeth C Mormino^{3

13}, Katrin I Andreasson^{3

13

15}

Affiliations

¹ Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA. enwilson@stanford.edu.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. enwilson@stanford.edu.
³ Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA.
⁴ Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
⁵ Fujirebio Europe NV, Ghent, Belgium.
⁶ Psychology, Stanford University, Stanford, CA, USA.
⁷ Neurology, Portland VA Medical Center, Portland, OR, USA.
⁸ Neurology, Oregon Health & Science University, Portland, OR, USA.
⁹ Pathology, Stanford University, Stanford, CA, USA.
¹⁰ Psychiatry, Yale University, New Haven, CT, USA.
¹¹ Biomedical Data Science, Stanford University, Stanford, CA, USA.
¹² Radiology, Stanford University, Stanford, CA, USA.
¹³ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
¹⁴ Epidemiology & Population Health, Stanford University, Stanford, CA, USA.
¹⁵ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.

PMID: 36371232
PMCID: PMC9652927
DOI: 10.1186/s13195-022-01116-2

Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease

Edward N Wilson et al. Alzheimers Res Ther. 2022.

. 2022 Nov 12;14(1):172.

doi: 10.1186/s13195-022-01116-2.

Authors

Affiliations

¹ Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA. enwilson@stanford.edu.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. enwilson@stanford.edu.
³ Neurology & Neurological Sciences, Stanford University, Stanford, CA, USA.
⁴ Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
⁵ Fujirebio Europe NV, Ghent, Belgium.
⁶ Psychology, Stanford University, Stanford, CA, USA.
⁷ Neurology, Portland VA Medical Center, Portland, OR, USA.
⁸ Neurology, Oregon Health & Science University, Portland, OR, USA.
⁹ Pathology, Stanford University, Stanford, CA, USA.
¹⁰ Psychiatry, Yale University, New Haven, CT, USA.
¹¹ Biomedical Data Science, Stanford University, Stanford, CA, USA.
¹² Radiology, Stanford University, Stanford, CA, USA.
¹³ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
¹⁴ Epidemiology & Population Health, Stanford University, Stanford, CA, USA.
¹⁵ Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA.

PMID: 36371232
PMCID: PMC9652927
DOI: 10.1186/s13195-022-01116-2

Abstract

Background: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.

Methods: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid β peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.

Results: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aβ42/Aβ40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aβ+ and Aβ- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.

Conclusions: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

Keywords: Alzheimer’s disease; Biomarkers; Phospho-tau; Plasma.

PubMed Disclaimer

Conflict of interest statement

MV and NLB are employees of Fujirebio. The other authors declare that they have no competing interests.

Figures

**Fig. 1**
Plasma p-tau181 distinguishes Aβ− CU from Aβ+ AD. A Plasma p-tau181 was highest in AD (n = 78) followed by MCI (n = 107) and CU (n = 463) groups. B Plasma p-tau181 was higher in groups with increasing copy number of the *APOE* ε4 allele in CU and MCI. C Classification of participants by amyloid-positivity revealed plasma p-tau181 was elevated in Aβ+ CU and Aβ+ MCI as well as in Aβ+ AD. D ROC curve analysis of p-tau181 in distinguishing AD cases from Aβ− CU controls. E The Youden method was used to determine optimal cutpoint maximizing sensitivity and specificity for distinguishing Aβ+ AD cases from Aβ− CU. Log₁₀-transformed plasma p-tau 181 data analyzed using ANCOVA with age and sex included as cofactors. Tukey’s post hoc test was used for pairwise comparisons (A–C). Data presented as mean ± SD

**Fig. 2**
Plasma p-tau181 associates with amyloid and tau CSF biomarkers. A Plasma p-tau181 was higher in CSF Aβ+ (n = 92) compared to Aβ− participants (n =179). B Plasma p-tau181 was positively associated with CSF Aβ42/Aβ40 ratio overall and after stratifying participants according to CSF Aβ+ (orange circles), as well as in Aβ− participants (blue circles). C Plasma p-tau181 was significantly associated with CSF p-tau181 overall and again in both Aβ+ and Aβ− participants. Raw data are presented as mean ± SD (A) or plotted with the 95% confidence band of the best-fit line with Pearson correlation coefficient r, and β estimates and p-value from linear regression models with age and sex as covariates (B and C). n = 92 (CSF Aβ+) and n = 179 (CSF Aβ−)

**Fig. 3**
Plasma p-tau181 associates with amyloid PET. Amyloid PET neuroimaging with Florbetaben revealed that plasma p-tau181 was significantly higher in amyloid PET+ (n = 25) compared to amyloid PET− (n = 35) participants (A) and positively associated with global amyloid PET (B). Raw data are presented as mean ± SD (A) or plotted with the 95% confidence band of the best-fit line with Pearson correlation coefficient r, and β estimates and p-value from linear regression models with age and sex as covariates (B)

**Fig. 4**
Plasma p-tau181 increases with time in CU and AD diagnostic groups. Change in plasma p-tau181 over time was significantly different than zero in CU and AD diagnostic groups. Shown are the p-values and the unstandardized regression co-efficient (β)

**Fig. 5**
Plasma p-tau181 associates with cognitive and functional measures of AD. A Higher baseline plasma p-tau181 was associated with worse baseline cognition measured by the MoCA for the AD group only and this association was significantly stronger for AD compared to CU and MCI groups. B Higher baseline plasma p-tau181 was associated with worse baseline functioning measured by the CDR for MCI and AD groups, and this association was significantly stronger for AD compared to CU and MCI groups. C Higher baseline plasma p-tau181 was associated with greater cognitive decline overall and this association was stronger for MCI than CU. D Higher baseline plasma p-tau181 was associated with greater functional decline in the AD group. All depicted residual values were controlled for age, sex, and education; change in MoCA and CDR per year was calculated for visualization purposes only

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Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease

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Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease

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