Temporal Dynamics and Biological Variability of Alzheimer Biomarkers

Importance: Understanding the characteristics of discordance between plasma biomarkers and positron emission tomography (PET) results in Alzheimer disease (AD) is crucial for accurate interpretation of the findings. Objective: To compare (1) medical comorbidities affecting plasma biomarker concentrations, (2) imaging and clinical features, and (3) cognitive changes between plasma biomarker and PET discordant and concordant cases. Design, Setting, and Participants: This multicenter cohort study, conducted between 2016 and 2023, included individuals with unimpaired cognition, mild cognitive impairment, or Alzheimer-type dementia, who had both amyloid β (Aβ) PET imaging and plasma biomarkers. A subset of participants also underwent tau PET imaging. Exposures: Participants were categorized into 4 groups based on their plasma and PET biomarker results: plasma-/PET-, plasma+/PET-, plasma-/PET+, and plasma+/PET+. Main Outcomes and Measures: Clinical characteristics were compared between the 4 groups, focusing on the discordant groups. Results: A total of 2611 participants (mean [SD] age was 71.2 [8.7] years; 1656 female [63.4%]), of whom 124 additionally underwent tau PET, were included. Among the plasma biomarkers, phosphorylated tau (p-tau) 217 exhibited the highest concordance rate with Aβ (2326 of 2571 [90.5%]) and tau (100 of 120 [83.3%]) PET. The p-tau217+/Aβ PET- group was older (mean [SD] age, 75.8 [7.2] years vs 70.0 [8.8] years; P < .001) with a higher prevalence of hypertension (56 of 152 [36.8%] vs 266 of 1073 [25.0%]), diabetes (40 of 152 [26.3%] vs 156 of 1059 [14.7%]), and chronic kidney disease (17 of 152 [11.2%] vs 21 of 1073 [2.0%]) compared with the p-tau217-/Aβ PET- group (P < .001 for all). Body mass index was higher in p-tau217-/Aβ PET+ than in p-tau217+/Aβ PET+ (mean [SD], 24.1 [2.8] vs 23.1 [3.1], respectively; P = .001; calculated as weight in kilograms divided by height in meters squared). The p-tau217+/Aβ PET- group had lower hippocampal volume (mean [SD], 2555.4 [576.9] vs 2979.1 [545.8]; P < .001) and worse clinical trajectory compared with p-tau217-/Aβ PET- (β = -0.53; P < .001). In contrast, tau PET discordant cases did not show significant differences in medical comorbidities or clinical outcomes compared with the p-tau217-/tau PET- group. Only the p-tau 217+/tau PET+ group demonstrated faster cognitive deterioration compared with the p-tau 217-/tau PET- group (β = -1.66; P < .001). Conclusions and Relevance: Results of this cohort study suggest that the mechanisms underlying the discordance between plasma biomarkers and PET findings may be multifaceted, underscoring the need to consider the temporal dynamics and biological variability of plasma biomarkers.