Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Abstract

Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

“…Our Aβ ସଶ /Aβ ସ AUC is consistent with the AUC reported in other studies of cognitively normal individuals based on Simoa immunoassays [15,33]. Our findings also corroborate previous studies indicating that plasma p-tau measures more closely reflect brain amyloid levels compared to plasma measures of amyloid [16] and that p-tau231 has the highest AUC at the preclinical stage [14][15][16]. As expected, based on our univariate results, plasma p-tau, specifically p-tau231, and Aβ measures were the most important variables in the best multivariate classifier, which outperformed univariate classifiers and had a sensitivity and specificity of about 80% at its optimal operating point.…”

“…In a cohort that included individuals with and without cognitive impairment, Rauchmann et al examined trajectories of plasma p-tau181 and NfL relative to cerebrospinal fluid or imaging measure-based definitions of amyloid (A), tau (T), and neurodegeneration (N) status and found that relative to the A−TN− group, all other groups exhibited steeper longitudinal increases in NfL [13]. Further, recent cross-sectional and longitudinal studies have shown early changes of all plasma biomarkers but note that p-tau231 changes earliest in response to Aβ deposition [14–16]. These findings suggest that these plasma biomarkers may be dynamic in the preclinical phase of AD and even earlier.…”

The dynamics of plasma biomarkers across the Alzheimer’s continuum

“…This further emphasizes the value of plasma GFAP in uncovering AD-related neuropathological changes. As a growing number of studies demonstrated the great promise of plasma p-tau231 and p-tau217 in the early identification of AD pathophysiology [ 12 , 21 – 23 ], their inclusion in the analysis may yield intriguing results. However, limited by the current technical conditions, we are unable to quantify their concentrations.…”

“…This is in line with the previously reported dynamics across the clinical spectrum of AD [ 19 ] and the comparable concentrations of plasma Aβ in AD and controls [ 43 ], supporting that plasma Aβ levels might reflect peripheral Aβ generation more than they reflect AD brain pathology [ 19 ]. However, other studies demonstrated the potential of plasma Aβ markers in capturing early cerebral Aβ changes [ 10 , 22 , 23 ]. With the development of technology, recent studies have revealed that mass spectrometry-based methods outperform most immunoassays in the precise assays of plasma Aβ [ 44 – 46 ].…”

“…On the other hand, many studies included a single or very low number of markers but ignored the head-to-head comparison with other biomarkers [ 11 , 21 ], hence the relative orderings of biomarker changes couldn’t be derived. Recent studies overcame both of the above shortcomings, but they examined only the preclinical stage of AD [ 22 ] or preclinical and prodromal stages [ 23 ] and lacked an understanding of the whole AD continuum. In addition, these former studies are primarily from western countries, how early the blood biomarkers begin to change, their characteristics of alterations, and whether these biomarkers reflect AD pathologies within the Chinese population is unclear.…”