Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease

Abstract

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1-42 (Aβ1-42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Figure 1

Histograms of predicted mean plasma biomarker concentrations in mutation non-carriers and carriers at select levels of estimated years to symptom onset (EYO) as determined by general linear mixed models, accounting for within-family dependencies. Estimated trajectories of plasma (A) Aβ1-40, (B) Aβ1-42, (C) the ratio of Aβ1-42/1-40 and (D) VILIP-1 are shown for mutation non-carriers (NC, hatched) and mutation carriers (MC, solid). Values represent mean ± SE. MC significantly different from NC at a given EYO at *p<0.05, **p<0.01, †p<0.001, ††p<0.0001.

Figure 2

Histograms of predicted mean CSF biomarker concentrations in mutation non-carriers and carriers at select levels of estimated years to symptom onset (EYO) as determined by general linear mixed models, accounting for within-family dependencies. Estimated trajectories of CSF (A) Aβ1-40, (B) Aβ1-42, (C) tau, (D) ptau181, (E) tau/Aβ1-42 ratio, (F) ptau181/Aβ1-42 ratio, (G) VILIP-1 and (H) VILIP-1/ Aβ1-42 ratio are shown for mutation non-carriers (NC, hatched) and mutation carriers (MC, solid). Values for Aβ1-42 were obtained with AlzBio3. Values represent mean ± SE. MC significantly different from NC at a given EYO at *p<0.05, **p<0.01, †p<0.001, ††p<0.0001.

Figure 3

Association between fluid Aβ measures and mean cortical PIB retention in mutation non-carriers and carriers. Concentrations of CSF (A, B) Aβ1-40 and (C, D) Aβ1-42, and concentrations of plasma (E, F) Aβ1-40 and (G, H) Aβ1-42 are shown for mutation non-carriers (NC, left column) and carriers (MC, right column). Units on the Y axes are pg/mL. Units on the X-axes are mean cortical PIB standardized uptake value ratio (SUVR) calculated from prefrontal cortex, gyrus rectus, lateral temporal and precuneus regions using a brainstem (pons) grey matter reference following application of partial volume correction. Cortical PIB-positivity in this ADAD cohort is defined as SUVR ≥0.85 (vertical dashed line) based on a k-means clustering algorithm implemented in R (see Materials and Methods section). Symbol colors identify groupings of the estimated years to symptom onset (EYO) in the participant groups, with blue-to-red gradations extending from dark blue (EYO earlier than −20 years) to dark red (EYO later than +11 years).

Figure 4

Evaluation of CSF biomarker change over disease progression in mutation non-carriers and carriers as estimated from cross-sectional baseline measures from individuals at different stages of dementia severity. Box and whisker plots (median ± 25^th/75^th percentiles) of CSF (A) Aβ1-42, (B) tau, (C) ptau181 and (D) VILIP-1 obtained at baseline are shown for mutation non-carriers (NC, white box, as the normal reference group) and mutation carriers (MC, grey boxes) with the indicated Clinical Dementia Rating scores (CDR 0=cognitively normal; 0.5=very mild; 1=mild; 2=moderate; 3=severe). The number of participants in each group is shown in italics in parentheses. Units on Y axes are pg/mL. Horizontal lines indicate statistical significance between the groups as determined by general linear mixed models, accounting for within-family dependencies: * P<0.05, ** p<0.01, *** p<0.001, **** p<0.0001; Different from NC: + P<0.05, ++ p<0.01, +++ p<0.001, ++++ p<0.0001.

Figure 5

Evaluation of CSF biomarker change over time in mutation non-carriers (NC) and mutation carriers (MC) in the longitudinal cohort. Concentrations of CSF (A) Aβ1-42, (B) tau, (C) ptau181 and (D) VILIP-1 are shown as a function of the estimated years to symptom onset (EYO) at the time of sample collection. In order to maintain participant and investigator blinding to mutation status, only the estimated age at symptom onset (vertical dashed line, EYO=0) is shown. Top(s), spaghetti plots show individual data points, Bottom(s), histograms show the associated estimated mean (SE) annual within-individual rate of change in biomarker concentrations in the two genetic groups in the period prior to their estimated age at symptom onset (EAO, EYO≤0) or the period after their EAO (EYO>0). General linear mixed models were utilized that allowed for different slopes in the genetic groups, as well as based on where participants fell with respect to their estimated years to symptom onset at baseline (EYO≤0 vs EYO>0). In order to account for the within-individual and within-family correlations, the models incorporated random intercepts/slopes at the individual level and a random intercept at the family level. Blue, NC; red, MC. Italicized numbers above the mean group slopes correspond to the significant or near significant p values comparing the slopes to zero. Italicized numbers above the horizontal lines correspond to the significant p values comparing the slopes between the NC and MC groups within the indicated EYO range (EYO≤0 vs EYO>0).