Plasma phosphorylated tau 181 predicts amyloid status and conversion to dementia stage dependent on renal function

Abstract

BackgroundPlasma 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.MethodsThis 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.FindingsAmong 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.InterpretationPlasma 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.

Blood biomarkers: ready for clinical practice?

“…To this end, here, we present three papers that illuminate the practical application of blood biomarkers—Altomare et al 7 (Geneva Cohort) and Lehman et al 8 (BALTAZAR cohort) assess the performance of AD blood biomarkers in memory clinics, and Veria et al 9 highlight potential for positive AD blood biomarkers in amyotrophic sclerosis.…”

Clinical value of plasma ALZpath pTau217 immunoassay for assessing mild cognitive impairment

“…Other parameters such as age or BMI can also confound the value of AD prognostic biomarkers. For pTau181, we previously found impaired renal function likely undermines diagnostic performance 32 . In the same cohort, we now study pTau217 and we observed that renal function and other potential confounding factors have a minimal effect on its performance.…”

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy

“…These results further emphasize the importance of standardizing assays and procedures for plasma biomarkers in future research and clinical settings. Moreover, plasma biomarker levels and their diagnostic accuracy appear to be affected by multiple comorbidities 41,42 and peripherally derived plasma biomarkers 43,44 . Therefore, comprehending the impact of these comorbidities on plasma levels is also crucial for their prospective interpretation in the context of clinical screening, diagnosis, or prognosis at the population level.…”