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

• Background: 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. © 2022

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Alzheimer's disease

Amyloid

Cerebrospinal fluid

Phosphorylated tau

Positron emission tomography

Preclinical

amyloid beta protein

biological marker

epitope

flutafuranol

glycogen synthase kinase

tau 217

tau 231

tau protein

unclassified drug

adult

aged

aging

Alzheimer disease

Article

cognition

cognitive defect

cohort analysis

computer language

controlled study

dementia

diagnostic accuracy

diagnostic test accuracy study

enzyme linked immunosorbent assay

epitope mapping

female

frontotemporal dementia

human

image analysis

male

middle aged

neurofibrillary tangle

pathology

posterior cingulate

protein phosphorylation

quality control

receiver operating characteristic

sensitivity and specificity

Publikations- och innehållstyp

ref (ämneskategori)

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