Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes

Abstract

Objective: In the 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, 18 F-fluorodeoxyglucose-positron emission tomography, and brain atrophy. We aimed to assess the clinical outcomes of having discordant Alzheimer's neurodegenerative biomarkers. Methods: A total of 721 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative database were included and then further categorized into concordant-negative, discordant, and concordant-positive groups. Demographic distributions of the groups were compared. Longitudinal changes in clinical outcomes and risk of conversion were assessed using linear mixed-effects models and multivariate Cox proportional hazard models, respectively. Results: Discordant group was intermediate to concordant-negative and concordant-positive groups in terms of APOE e4 positivity, CSF amyloid-beta, and phosphorylated tau. Compared with concordant-negative group, discordant group deteriorated faster in cognitive scores (Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Functional Activities Questionnaire) and demonstrated greater rates of atrophy in brain structures (hippocampus, entorhinal cortex, and whole brain), and concordant-positive group performed worse over time than discordant group. Moreover, the risk of cognitive decline increased from concordant-negative to discordant to concordant-positive. The results from longitudinal analyses were validated in A+T+, cognitively normal, and mild cognitive impairment individuals, and were also validated by applying different cutoffs and neurodegenerative biomarkers. Interpretation: Discordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant-negative and concordantpositive. Identification of discordant cases would provide insights into intervention and new therapy approaches, particularly in A+T+ individuals. Moreover, this work may be a complement to the ATN scheme.

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline

“…There is, however, some support that HV is associated with cognitive decline and progression more strongly than t-tau. 13 - 15 Although in our study we found t-tau as individual biomarker also predicted clinical progression and cognitive decline, the high correlation with p-tau hampers the addition of t-tau to a model with Aβ and p-tau, making it a less desirable biomarker to use in the AT(N) classification. NfL and GFAP have both been shown to be related to baseline cognition, cognitive decline, and clinical progression as individual predictors, but have not yet been studied extensively in comparison to other N biomarkers.…”

“…The low correlation between N biomarkers likely contributes to the often discordant biomarker results in the AT(N) classification. 6 , 9 , 12 , 15 We add blood-based biomarkers to the comparison, showing similarly modest associations with the N biomarkers in other modalities, and also similarly strong associations with clinically relevant outcomes. Although at a population level, the overall qualitative pattern of biomarker frequencies remains rather stable regardless of the type of biomarkers used, 9 it becomes problematic when researchers and clinicians treat the different N biomarkers as if they were identical.…”

“…The low correlation between N biomarkers likely contributes to the often discordant biomarker results in the AT(N) classification. 6,9,12,15 We add blood-based biomarkers to the comparison, showing similarly modest associations with the N biomarkers in other modalities, and also similarly strong associations with clinically relevant outcomes.…”

“…Most are hampered by small sample sizes, and none has directly compared bloodbased biomarkers with CSF and imaging biomarkers. 10,[12][13][14][15] It is difficult to determine which modality captures neurodegeneration (N) most accurately, because there is no gold standard available. However, it should capture a different process than the accumulation of Aβ (A) or fibrillary tau (T), as otherwise the addition of N would have no added value in the AT(N) classification.…”

“…Most are hampered by small sample sizes, and none has directly compared blood-based biomarkers with CSF and imaging biomarkers. 10,12-15…”