Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease

Abstract

Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are accurate biomarkers for a pathological and clinical diagnosis of Alzheimer's disease (AD) and are seen to be increased in preclinical stage of the disease. However, it is unknown if these increases transpire earlier, prior to amyloid-beta (Aβ) positivity as determined by position emission tomography (PET), and if an ordinal sequence of p-tau epitopes occurs at this incipient phase METHODS: We measured CSF concentrations of p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum who had undergone Aβ ([¹⁸F]AZD4694) and tau ([¹⁸F]MK6240) position emission tomography (PET) and clinical assessment FINDINGS: All CSF p-tau biomarkers were accurate predictors of cognitive impairment but CSF p-tau217 demonstrated the largest fold-changes in AD patients in comparison to non-AD dementias and cognitively unimpaired individuals. CSF p-tau231 and p-tau217 predicted Aβ and tau to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was sensitive to the earliest changes of Aβ in the medial orbitofrontal, precuneus and posterior cingulate before global Aβ PET positivity was reached INTERPRETATION: We demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application FUNDING: Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Weston Brain Institute, Brain Canada Foundation, the Fonds de Recherche du Québec.

Keywords: Alzheimer's disease; Amyloid; Cerebrospinal fluid; Phosphorylated tau; Positron emission tomography; Preclinical.

Figure 1

Phosphorylated tau CSF epitopes by group. Distribution of CSF biomarkers concentrations across groups showing higher biomarker levels associated with Aβ positivity. CU-: cognitively unimpaired Aβ negative; CU+: cognitively unimpaired Aβ positive; CI-: cognitively impaired Aβ negative; CI+: cognitively impaired Aβ positive; MCI+: mild cognitively impaired Aβ positive; AD: Alzheimer's disease dementia; Non-AD: mild cognitively impaired Aβ negative and frontotemporal dementia (FTD). ^⁎⁎⁎P<0.001; ^⁎⁎P<0.01; *P<0.05 (Tukey HSD adjusted).

Figure 2

Phosphorylated tau CSF epitopes and Tau PET associations. Spearman rank correlations between CSF biomarkers and tau PET ([¹⁸F]MK6240) across all groups show p-tau231 as having the highest correlation coefficient, followed by p-tau217 (a–c). The accuracy of CSF biomarkers in distinguishing tau PET status (positive vs negative) is evidenced by AUCs as shown in (d). T-parametric maps show the voxel-wise association between CSF biomarkers and [¹⁸F]MK6240 in all participants (e) as well as within CI (f) and CU (g). Models were adjusted for age and sex and RFT was used to account for multiple comparisons (significant t-values > 3.1). CU: cognitively unimpaired; CI: cognitively impaired.

Figure 3

Phosphorylated tau CSF epitopes and Aβ PET associations. Spearman rank correlations between CSF biomarkers and Aβ PET ([¹⁸F]AZD4694) across all groups show p-tau231 as having the highest correlation coefficient (a-c). The accuracy of CSF biomarkers in distinguishing Aβ PET status (positive vs negative) is evidenced by AUCs as shown in (d). T-parametric maps show the voxel-wise association between CSF biomarkers and [¹⁸F]AZD4694 in all participants (e) as well as within CI (f) and CU (g). Models were adjusted by age and sex and RFT was used to account for multiple comparisons (significant t-values > 3.1). The dot plot (h) shows the average slope (beta) values by ROI for each of the CSF biomarkers. The beta value was derived from linear models that had Aβ PET as the outcome measure, the CSF biomarkers were the predictors and the covariates were sex and age. These models were performed at the voxel level and the CSF p-tau beta values of each voxel were averaged within ROIs. Were included in the ROIs only the voxels that had a significant association between Aβ PET and all of the CSF biomarkers evaluated here. T-parametric maps (i) show the voxel-wise association between CSF biomarkers (p-tau231, p-tau217 and p-tau181) and [¹⁸F]AZD4694 in Aβ-negative CU subjects. Models were adjusted for age and sex and RFT was used to account for multiple comparisons (significant t-values > 3.1). In addition, CSF p-tau biomarkers were plotted (j) as a function of Aβ PET deposition (in Centiloids) in the CU group, which was used to infer AD pathology progression. Dashed line indicates the biomarker cut off for positivity. CU: cognitively unimpaired; CI: cognitively impaired.

Figure 4

P-tau231 as an early biomarker of Aβ pathology. The theoretical framework proposed presents a temporarily ordered progression of CSF p-tau epitopes in the context of the AD continuum, in which we hypothesize CSF p-tau231 as the first biomarker to become altered in the pre-amyloid phase, being then followed by p-tau217 and p-tau181 at pre-clinical and clinical stages.