The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease

Abstract

Introduction This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD.

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…The high analytical sensitivity (< 1 pg/mL) of the single-molecule array (Simoa) allows for predilution of samples that may reduce matrix effects. Subsequently, using this technique for Aβ [63], a significantly lower plasma Aβ42/40 ratio was found in both MCI and AD cases as compared with controls [25,64]. Furthermore, marginally improved associations were found with CSF Aβ and amyloid PET [64].…”

“…For IPMS studies, the AUC for Aβ42 ranges from 72-87% [67,87], between 80-97% for Aβ42/Aβ40 [66,67,86,87] and between 82-97% for the APP669-711/Aβ42 [67,87]. In contrast, accuracies of between 60-64% and 62-68% have been reported for the commercially available Simoa assays [25,64,103], although higher AUCs were achieved for a modified version of the Simoa assay which utilized differing antibodies [102]. Plasma Aβ42/Aβ40 measured by the fully automated Elecsys assay predicts Aβ status with an accuracy > 80% [85].…”

“…Though we recognize that neurofilament light (NfL) and total tau (t-tau) have been widely investigated in the context of AD, they are not considered in this review due to nondisease specificity for AD (NfL) or lack of clear disease association (t-tau). Concentrations of blood (plasma or serum) NfL have been shown to be robustly, albeit moderately, increased in MCI and AD [21][22][23][24][25]. Yet, NfL is a well-established measure of global neuronal injury in many neurodegenerative diseases [26,27] and acute neurological disorders [28].…”

“…Thus, NfL does not have the required specificity to be classified as an "AD biomarker". Plasma t-tau has also been investigated widely in AD [25,29,30], yet these studies have concluded that plasma t-tau, certainly in its current immunoassay format, only shows minor changes with large overlaps with disease controls to have clinical relevance for AD. Recent studies, despite being preliminary, have suggested that associations with AD can be achieved by measuring t-tau using an assay format directed toward the N-terminal region of the tau protein in blood [31,32].…”

Ultrasensitive assays for detection of plasma tau and phosphorylated tau 181 in Alzheimer’s disease: a systematic review and meta-analysis

“…These latest studies have investigated the dynamic changes of plasma ptau181 across the AD spectrum [100] and the relationship between polygenic risk scores for AD and plasma ptau181 [101]. They have also compared performance of ptau181 with other biomarkers in AD and MCI prediction [102] or amyloid PET status prediction [103]. In addition, ptau217 [104] and ptau231 (Ashton et al in press) have been reported recently to differentiate AD from other neurodegenerative disorders and be associated with tau pathology in the brain.…”