Timing of Alzheimer's disease biomarker progressions: A two-decade observational study from the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Abstract

Introduction: Alzheimer's Disease Neuroimaging Initiative (ADNI) has been pivotal in identifying and refining Alzheimer's disease (AD) biomarkers for clinical trials. This study leverages longitudinal data from participants who have progressed to amyloid-positivity during their study participation to track evolution of biomarkers and cognitive function.

Methods: We modeled AD biomarker (positron emission tomography [PET], structural, cerebrospinal fluid [CSF], cognition) trajectories before and after observed amyloid-positivity onset time to detect time at which each biomarker had detectable trajectory changes.

Results: Analysis of a sub-cohort of the 20-year ADNI study (N = 90) recapitulated Alzheimer's progression beginning with amyloid alterations -4.8 to -5.3 years relative to amyloid-positivity, succeeded by neurodegeneration (t = -4.0 to -4.1 years), and CSF tau (t = -0.4 to -0.5 years). Cognitive decline was observed to significantly correspond with emergence of amyloid-positivity (t = 0.2 to 2.4 years).

Discussion: Our results corroborate temporal progression curves of AD biomarkers, providing insights on earliest detectable changes in objective and subjective cognitive function assessments.

Keywords: amyloid phenotype progression; amyloid positivity; amyloid time; biomarker progression; subjective cognitive decline.

FIGURE 1

Flowchart showing selection process for participants. Participants must have had more than one amyloid PET scan and phenoconverted from amyloid− to amyloid+ during their participation in ADNI to be included in this study. ADNI, Alzheimer's Disease Neuroimaging Initiative; PET, positron emission tomography.

FIGURE 2

Generalized additive model (GAM) fits for PET, CSF, and MRI biomarker measures as a function of amyloid time (i.e., years from amyloid positivity). Bold areas of curves represent areas where the slope is significantly different from zero. Dashed vertical lines indicate the points in amyloid time at which the slopes become significant. Raw data plots are provided in Figure S1. CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography.

FIGURE 3

Generalized additive model (GAM) fits for global, domain‐specific, and subjective cognition measures. Bold areas of curves represent areas where the slope is significantly different from zero. Dashed vertical lines indicate the points in amyloid time at which the slopes become significant. Raw data plots are provided in Figure S2.