Associations Between Changes in Levels of Phosphorylated Tau and Severity of Cognitive Impairment in Early Alzheimer Disease
Fernando González‐Ortiz, Bjørn‐Eivind Kirsebom, Yara Yakoub, J Gundersen, Lene Pålhaugen, Knut Waterloo, Per Selnes, Jonas Alexander Jarholm, Berglind Gísladóttir, Arvid Rongve, Ragnhild Eide Skogseth, Geir Bråthen, Dag Aarsland, Michael Turton, Peter Harrison, Henrik Zetterberg, Sylvia Villeneuve, Tormod Fladby, Kaj Blennow
Abstract
BACKGROUND AND OBJECTIVES: Aligning biomarker evidence with clinical presentation in early Alzheimer disease (AD) is essential for improving diagnosis, prognosis, and interventions. This study evaluates the relationship between cognitive impairment, future decline, and phosphorylated tau levels in plasma and CSF in predementia AD. METHODS: This longitudinal observational study included predementia cases and controls from 2 independent cohorts: the Norwegian Dementia Disease Initiation (DDI) and Canadian Pre-Symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD). In DDI, cognitively normal (CN) and mild cognitive impairment (MCI) cases were classified using CSF Aβ42/40 ratio (A) and p-tau181 (T), whereas classification in PREVENT-AD (A) was based on amyloid PET scans. In DDI, we assessed CSF-plasma correlations for p-tau181, p-tau217, and p-tau231. Diagnostic accuracies were evaluated through receiver operating characteristic analyses. Linear mixed models evaluated p-tau associations with future memory decline. Between-group differences in plasma p-tau217 were assessed in both cohorts. RESULTS: < 0.05). DISCUSSION: Our findings suggest that, unlike p-tau181 and p-tau231, plasma p-tau217 consistently aligns with cognitive status in A+ individuals and better reflects CSF biomarker abnormalities, reducing discrepancies between clinical and biochemical findings. Its association with baseline and future memory decline highlights its diagnostic and prognostic value, particularly when CSF analysis or PET is unavailable.