Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Abstract

Objective: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.

Methods: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.

Results: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations.

Conclusion: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

© 2018 American Academy of Neurology.

Figures

Figure 1. Individual longitudinal imaging, CSF, and clinical measures over estimated year to symptom onset (EYO) for mutation carriers and noncarriers

(A–H) Individual longitudinal changes for all CSF, imaging, and clinical biomarkers for mutation carriers (red) and noncarriers (blue). To maintain blinding of genetic status, the values of the x-axis (EYO) have been removed. The black vertical line represents the point of estimated symptom onset. Aβ = β-amyloid; CDR = Clinical Dementia Rating scale; FDG = fluorodeoxyglucose; p-tau = phosphorylated tau; PiB = Pittsburgh compound B; SUVR = standardized uptake value ratio.

Figure 2. Model estimated individual rate of change for all imaging, CSF, and clinical measures over estimated year to symptom onset (EYO) for mutation carriers and noncarriers

(A–H) Each point represents an individual's model estimated rate of change with their baseline EYO at the time of study entry. For each individual, the annualized rate of change is estimated in the units of measurement for each variable. The solid lines represent the LOESS for mutation carriers (red) and noncarriers (blue). Aβ = β-amyloid; CDR = Clinical Dementia Rating scale; p-tau = phosphorylated tau.

Figure 3. Comparison of cross-sectional and longitudinal estimated rates of change for imaging, CSF, and clinical measures in mutation carriers over estimated year to symptom onset (EYO)

Clinical, cognitive, and biomarker measures across baseline EYO based on cross-sectional estimates (red line) and 5-year calculated longitudinal trajectories (black line) modeled from the longitudinal data. The longitudinal trajectory is estimated using the rate of change from the mixed effects model over the 5 years. These findings indicate consistent cross-sectional estimates with longitudinal confirmation for Pittsburgh compound B PET; however, in other measures, cross-sectional data underestimate the rate of change measured by longitudinal measures, with rapid changes noted in clinical measures, CSF tau, and brain atrophy. Aβ = β-amyloid; CDR = Clinical Dementia Rating scale; p-tau = phosphorylated tau.