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- Title
Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment.
- Authors
Janelidze, Shorena; Barthélemy, Nicolas R.; Salvadó, Gemma; Schindler, Suzanne E.; Palmqvist, Sebastian; Mattsson-Carlgren, Niklas; Braunstein, Joel B.; Ovod, Vitaliy; Bollinger, James G.; He, Yingxin; Li, Yan; Raji, Cyrus A.; Morris, John C.; Holtzman, David M.; Ashton, Nicholas J.; Blennow, Kaj; Stomrud, Erik; Bateman, Randall J.; Hansson, Oskar
- Abstract
This cohort study investigates the utility of plasma markers phosphorylated tau 217 (p-tau217) and β-amyloid 42/40 (Aβ42/40) to predict development of Alzheimer disease–related Aβ pathology in cognitively unimpaired individuals with low brain Aβ levels. Key Points: Question: Which plasma biomarkers are useful to predict future development of Alzheimer disease (AD)–related β-amyloid (Aβ) pathology in cognitively unimpaired individuals (CU) with low brain Aβ levels? Findings: In this cohort study, which included CU individuals from 3 independent cohorts (the Swedish BioFINDER-2 study, Knight Alzheimer Disease Research Center, and the Swedish BioFINDER-1 study), a combination of baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 better predicted longitudinal changes in brain Aβ load than individual biomarkers in 514 participants with low brain Aβ levels at baseline. Meaning: Blood tests combining p-tau217 and Aβ42/40 levels could be useful for screening CU participants with early, subthreshold stages of brain Aβ pathology for future primary prevention trials in AD. Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve =0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = −1.64; 95% CI, −2.53 to −0.75; %p-tau217 × Aβ42/40: β = −2.14; 95% CI, −2.79 to −1.49; P <.001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = −0.33; 95% CI, −0.51 to −0.15; %p-tau217 × Aβ42/40: β = −0.31; 95% CI, −0.44 to −0.18; P <.001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P =.002; Aβ42/40: β = −0.74; 95% CI, −1.26 to −0.22; P =.006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = −0.0003; 95% CI, −0.0004 to −0.0001; P =.01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P <.001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.
- Publication
JAMA Neurology, 2024, Vol 81, Issue 9, p947
- ISSN
2168-6149
- Publication type
Article
- DOI
10.1001/jamaneurol.2024.2619