Background Plasma P-tau181 is associated with tau and amyloid pathology in Alzheimer's disease (AD). Its use as a biomarker for the detection of AD (along the disease continuum, from preclinical to mild cognitive impairment (MCI) and dementia) is increasingly established, as is its prognostic value. Further validation in different settings of use is still needed, as well as investigation of confounding factors that might indirectly influence its blood concentration. Methods This study is ancillary to the prospective multicenter BALTAZAR cohort that enrolled patients with MCI according to Petersen criteria. Amyloid-positive (Aβ+) status was based on assessment of the cerebrospinal fluid (CSF) Aβ1-42/Aβ1-40 ratio, and participants were examined for conversion to dementia for up to three years. Plasma Ptau-181 was measured using an ultrasensitive assay and its diagnostic performance for Aβ+ and conversion to dementia were studied, as well as evaluation of the impact of comorbidities and biological confounders. Findings Among 476 MCI participants (mean MMSE score of 26.4 [SD 2.5] and 39.8% carrying APOE ε4), 67% were Aβ+ and 30% developed dementia (95% probable AD) at a mean of 14.6 [SD 8.2] months after the baseline. Independently of age, sex, and APOEε4, plasma P-tau181 was increased significantly by 30% between non-converters and converters (2.9 [SD 1.4] vs. 3.8 [SD 1.5] pg/mL, p<0.0001) and by 50% between Aβ- and Aβ+ (2.6 [SD 1.4] vs. 3.9 [SD 1.4] pg/mL, p<0.0001). Logistic regression was used to compare conversion and Aβ+ detection combining age, sex, APOEε4 status and MMSE without or with the addition of plasma P-tau181 which significantly improves performance (AUC 0.691 to 0.744 for conversion and 0.786 to 0.849 for Aβ+). CSF P-tau181 did not perform better in the same setting. Using a linear regression approach, chronic kidney disease (CKD), creatinine and glomerular filtration rate were independently associated with plasma P-tau181 concentrations, thereby altering the optimal cutpoints for Aβ+ or conversion to dementia detection. Interpretation Plasma P-tau181 effectively detects Aβ+ and conversion to dementia in a manner similar to CSF P-tau181, making this blood biomarker central to AD management. However, renal function significantly alters concentrations and will induce diagnostic error if not systematically taken into account.

The authors have declared no competing interest.

https://clinicaltrials.gov/ct2/show/NCT01315639

This study was funded by: The French ministry of Health (Programme Hospitalier de Recherche Clinique), Grant-Award Numbers: PHRC2009-01-04,PHRC-13-0404; The Foundation Plan Alzheimer; Fondation pour la Recherche Medicale (FRM).

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All participants gave written informed consent to be part of the study. The BALTAZAR study was approved by the Paris ethics committee (CPP Ile de France IV Saint-Louis Hospital).

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