Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies

Abstract

Background: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes.

Objectives: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay.

Design: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks.

Setting: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia.

Participants: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553).

Measurements: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo).

Results: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models.

Conclusions: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Keywords: Amyloid; biomarkers; cognitive decline; imaging; tau.

Figure 1

Cognitive Change by Amyloid PET and Plasma P-tau217 levels Panel A depicts modeled mean Preclinical Alzheimer Cognitive Composite (PACC) for those in LEARN and each tertile of baseline amyloid PET in A4. Panel B depicts modeled mean PACC for those in LEARN and each tertile of baseline P-tau 217 using a similar approach. Panel C depicts the interaction of baseline amyloid PET and P-tau 217 levels. Each of the four panels of Panel C shows the modeled mean PACC change according to the tertiles of baseline P-tau217 within the indicated amyloid PET group. All models assumes a natural cubic spline for time with two degrees of freedom for per group and control for age, APOEε4 carrier status, education and PACC version; and all models assume heterogeneous Toeplitz variance-covariance. Shaded regions are 95% confidence intervals.

Figure 2

Functional Outcomes by amyloid PET and Plasma P-tau217 The Cognitive Function Index (CFI) combined participant and study partner trajectories for LEARN and A4 tertiles of baseline amyloid PET in Panel A and for plasma P-tau 217 in Panel D. Activities of Daily Living Prevention Instrument (ADL) study partner trajectories are shown by amyloid PET (Panel B) and plasma P-tau217 (Panel E). The Clinical Dementia Rating Sum of Boxes (CDR-SB) trajectories are shown by amyloid PET (Panel C) and P-tau217 (Panel F). Kaplan-Meier estimated Clinical Dementia Rating Global Score (CDR-GS) progression rates are shown by amyloid PET (Panel G) and P-tau 217 (Panel H). CDR-GS Progression is defined as two consecutive CDR-GS above 0, or final endpoint CDR-GS above 0. Shaded regions are 95% confidence intervals.

Figure 3

PACC Change Variance Explained Full Sample Across LEARN and A4 and within A4 Treatment Groups PACC change variance explained (R²) in LEARN and A4 (A: Top Row) and within and across A4 treatment arms (B: Bottom Row) by each baseline predictor, partitioned into common and unique (R²). Participant-specific summaries of PACC change from baseline at week 240 were estimated from linear mixed-effects models two spline basis expansion terms for time and adjusting for PACC test version and participant-specific random intercepts and slopes. These change scores were then submitted to ordinary least squares regression with each of the indicated baseline predictors. The R² from these models are indicated by the sum of light and dark blue bars, and the nominal p-value for each predictor is shown.

Figure 4

A4 Tau PET Substudy PACC Change Variance Explained PACC change variance explained (R²) in A4 Tau PET Substudy (N-350) by each baseline predictor considered partitioned into common and unique (R²), within and across A4 treatment arms. Participant-specific summaries of PACC change from baseline at week 240 are estimated from linear mixed-effects models two spline basis expansion terms for time and adjusting for PACC test version and participant-specific random intercepts and slopes. These change scores were then submitted to ordinary least squares regression with each of the indicated baseline predictors. The R² from these models are indicated by the sum of light and dark blue bars, and the nominal p-value for the predictor is shown.