The Computerized Cognitive Composite (C3) in A4, an Alzheimer’s Disease Secondary Prevention Trial

Abstract

Background: Computerized cognitive assessments may improve Alzheimer’s disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. Objective: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). Design: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). Setting: Multi-center international study. Participants: Clinically normal (CN) older adults (65-85; n=4486). Measurements: Participants underwent florbetapir-Positron Emission Tomography for Aβ+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer’s Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aβ+/- groups (n=1323/3163) and PACC. Results: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen’s d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. Conclusions: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Current advances in digital cognitive assessment for preclinical Alzheimer's disease

“…In a large sample of older adults ( n = 4486), C3 performance was shown to be moderately correlated with cognitive performance on a composite of paper‐and‐pencil measures (PACC). 7 A smaller study similarly showed this correlation between the C3 and paper‐and‐pencil measures. 58 It also showed that the Cogstate C3 battery's memory tasks were best at identifying individuals’ subtle cognitive impairment, as defined by PACC performance.…”

“…In clinically normal (CN) individuals, abnormal levels of Aβ (Aβ+), as measured in cerebrospinal fluid (CSF) (e.g., levels of Aβ 42 or Aβ 42/40 ) or with positron emission tomography (PET) neuroimaging, are considered indicative of an early AD pathological process. 2 , 3 During this preclinical stage of the disease continuum, the cross‐sectional association between Aβ and cognitive deficits is generally weak, 5 , 6 , 7 , 8 or insignificant. 9 , 10 , 11 However, CN individuals with higher Aβ burden (Aβ+) exhibit faster cognitive decline, 12 , 13 , 14 and often progress to a clinical stage faster than those with lower levels of Aβ.…”

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

“…Results from this 'Rate Of Change Sub-study' (AIBL-ROCS), confirmed that increased numbers of reassessments (i.e., > 8) improved sensitivity to A␤amyloid-related cognitive change in both preclinical and prodromal AD [63]. These data provided the foundation for the use of the CBB in other studies of AD genesis (e.g., the Mayo study of Health and Aging [64]) and in clinical trials designed to treat AD by clearing A␤-amyloid prior to the development of cognitive impairment (e.g., [65,66]).…”

Using Digital Tools to Advance Alzheimer’s Drug Trials During a Pandemic: The EU/US CTAD Task Force

“…Development of the C3 included its use in the A4 study, a secondary prevention trial in clinically normal older adults with abnormal levels of amyloid who were randomized to receive placebo or solanezumab. This initial study showed that when the drug was administered in screening period, the amyloid-positive group performed worse on C3 compared to the Preclinical Alzheimer Cognitive Composite (PACC) ( 16 , 17 ). The C3 has also been shown to provide reliable data when participants complete the assessments at home on an iPad ( 18 ).…”