Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome

Abstract

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73–0.87] and 0.92 [95% CI 0.89–0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.

Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

“…The accuracy was shown to be less when comparing controls with prodromal dementia (AUC = 0.80). This study concluded that plasma p-tau181 correlates with core fluid biomarkers of AD (CSF Aβ42/40, CSF t-tau, CSF NfL, and plasma NfL), as well as with atrophy in AD-related brain regions, including the temporal regions, angular and supramarginal gyri, and precuneus of both hemispheres (measured by MRI), and lower brain metabolism in temporoparietal regions (measured by FDG-PET) [90]. The latest research analyzing the association of the APOE genotype with AD biomarkers in patients with DS showed that APOE ε4 allele carriers showed earlier increases in plasma p-tau181, starting from the mid-40s and with confidence intervals not overlapping by age 50 years [45].…”

“…Furthermore, plasma GFAP has been recently reported to be a robust surrogate biomarker of amyloid pathology in sAD, independent of tau [126], and thus has potential to be a key biomarker in DS-AD. The emergence of p-tau181 as a biomarker for AD pathology is also showing usefulness in DS [90]. However, given that dementia in DS is highly likely to be due to AD, p-tau181 might not be superior to plasma NfL in this scenario-although more head-to-head studies including different p-tau epitopes (p-tau217 and p-tau231) are needed.…”

Commentary on Oeckl et al., “Serum Beta‐Synuclein Is Higher in Down Syndrome and Precedes Rise of pTau181”

“…Whilst reliable cerebrospinal fluid (CSF) and imaging biomarkers for AD pathologies and neurodegeneration have been available for some time, the field has recently been galvanized by the development of blood‐based biomarkers 4 . This is a rapidly evolving area of research with several studies pointing to plasma proteins changing prior to onset of dementia 5, 6 . Sensitive blood‐based assays for phosphorylated tau forms (pTau) for use as blood biomarkers of AD‐related tau pathophysiology have been developed.…”

“…4 This is a rapidly evolving area of research with several studies pointing to plasma proteins changing prior to onset of dementia. 5,6 Sensitive blood-based assays for phosphorylated tau forms (pTau) for use as blood biomarkers of AD-related tau pathophysiology have been developed. A ratio of 42 to 40 amino acid-long amyloid β (Aβ42/Aβ40) in plasma reflects cerebral Aβ pathology.…”

“…Additionally, plasma pTau181 has been proven to differentiate people with DS with and without dementia with high accuracy, but no better than NfL. 6 The high diagnostic performance of NfL, in addition to its stability in pre-analytical handling and the fact that it can be measured by robust assays used in clinical routine in many European countries, has pointed to plasma NfL as the best biomarker for diagnosis of AD in DS. 8 However, more studies are needed to determine if other biomarkers, different than those used for sAD-for example, related to synaptic, inflammatory, metabolic, or oxidative stress imbalances-could be earlier or more accurate biomarkers for dementia in DS.…”