A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS)

Abstract

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

Keywords: Alzheimer’s disease; clinical trials; iADRS; outcome measure.

Conflict of interest statement

Conflict of interests: A. M. Wessels, E. R. Siemers, P. Yu, S. W. Andersen, K. C. Holdridge, J. R. Sims, and K. Sundell are employees and minor shareholders of Eli Lilly and Company. Y. Stern reports personal fees from Eli Lilly and Company. D. M. Rentz reports consulting for Eli Lilly and Company. B. Dubois reports grants from Eli Lilly and Company and Pfizer. R. W. Jones reports grants from the UK Alzheimer’s Society, Economic and Social Research Council, and National Institute for Health Research; grants, personal fees, and non-financial support from Eli Lilly; grants, personal fees, and non-financial support from Servier; grants, personal fees, and non-financial support from Pfizer; personal fees and non-financial support from Lundbeck; personal fees and non-financial support from Novartis; grants from Genentech; grants from Boehringer Ingelheim; grants from Tau Rx; grants, personal fees, and non-financial support from AC Immune; and personal fees and non-financial support from Roche Pharmaceuticals. J. Cummings reports grants from from Avid Radiopharmaceuticals and Teva Pharmaceuticals; consultation to Abbvie, Acadia, ADAMAS, Alzheon, Anavex, Avanir, Biogen-Idec, Biotie, Boehinger-Ingelheim, Chase, Eisai, Forum, Genentech, Grifols, Intracellular Therapies, Lilly, Lundbeck, Merck, Neurotrope, Novartis, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Suven, Takeda, Toyoma, GE Healthcare, and MedAvante; stock ownership in ADAMAS, Prana, Sonexa, MedAvante, Neurotrax, and Neurokos; copyright ownership of the Neuropsychiatric Inventory; and expert witness consultation regarding olanzapine and ropinerol. P.S. Aisen reports grants from Eli Lilly and Company.

Figures

Figure 1

Signal-to-noise ratios (median and 2.5th percentiles) for mean change in outcome measures analyzed in the ADNI late MCI population (n=380), the ADNI mild AD population (n=181), and the solanezumab EXPEDITION and EXPEDITION2 Studies placebo mild AD (n=652), and moderate AD (n=334) populations Abbreviations: ADAS-Cog = Alzheimer’s Disease Assessment Scale-Cognitive subscale (11-, 13-, or 14-item version); ADCS-iADL = Alzheimer’s Disease Consortium Study-Activities of Daily Living, instrumental items; ADNI = Alzheimer’s Disease Neuroimaging Initiative; AVLTdelay = Auditory Verbal Learning Test Delayed Recall; AVLTimmed = Auditory Verbal Learning Test Immediate Recall; AVLTrecog = Auditory Verbal Learning Test Recognition; CDR-SB = Clinical Dementia Rating scale – Sum of Boxes; comp=composite; DIGITsymb = Digit Symbol Substitution; FAQ = Functional Activities Questionnaire; iADRS = integrated Alzheimer’s Disease Rating Scale; LMdelay = Logical Memory Delayed Recall; MCI-mild cognitive impairment; MMSE = Mini-Mental Status Examination; SNR = signal-to-noise ratios; V = version. * The different versions of the ADNI composites evaluated (designated as ADNI comp V1 through V5) represent measures of executive function (Digit Symbol Substitution), global cognition (MMSE), function (FAQ total score), and memory (ADNI comp V1: ADAS-Cog delayed word recall and logical memory delay; ADNI comp V2: logical memory delay and AVLT delayed recall; ADNI comp V3: logical memory delay, AVLT delayed recall, and AVLT immediate recall; ADNI comp V4: logical memory delay and AVLT immediate recall; and ADNI comp V5: logical memory delay, AVLT immediate recall, and retrieval efficiency [recognition minus delayed word recall]). The vertical lines mark the median of the ADAS-Cog13 (ADNI) or ADAS-Cog14 (EXPEDITION and EXPEDITION2) to aid in visual comparison among the scales.

Figure 2

Repeated measures analysis of ADAS-Cog14, ADCS-iADL, and iADRS in the pooled mild AD population from solanezumab EXPEDITION and EXPEDITION Studies Abbreviations: ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Consortium Study-Activities of Daily Living, instrumental items; iADRS = integrated Alzheimer’s Disease Rating Scale; LS = least squares. *=p<.05>

Figure 3

Repeated measures analysis of ADAS-Cog14, ADCS-iADL, and iADRS in the mild AD populations from solanezumab EXPEDITION and EXPEDITION2 Studies, by study Abbreviations: ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Consortium Study-Activities of Daily Living, instrumental items; iADRS = integrated Alzheimer’s Disease Rating Scale; LS = least squares. *=p<.05>

Figure 4

Delayed-start analysis of iADRS in the pooled mild AD population from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies Abbreviations: ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study – instrumental items of the Activities of Daily Living Inventory; DS = delayed start; ES = early start; EXP = EXPEDITION; EXP2 = EXPEDITION2; EXP-EXT = EXPEDITION-EXT; iADRS = integrated Alzheimer’s Disease Rating Scale; LS = least squares; NI = noninferiority criterion met. *=p<.05 primary delayed-start analysis time point circled.>

Figure 5

Repeated measures analysis of ADAS-Cog14, ADCS- iADL, and iADRS in the mild AD population from semagacestat IDENTITY Study Abbreviations: ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-iADL = Alzheimer’s Disease Cooperative Study – instrumental items of the Activities of Daily Living Inventory; iADRS = integrated Alzheimer’s Disease Rating Scale; LS = least squares. *=p<.05>

Figure 6

Repeated measures analysis of ADAS-Cog14, ADCS-MCI-ADL, and modified iADRS in the MCI+APOE ε4 carrier population from the donepezil ADCS-MCI Study Abbreviations: ADAS-Cog14 = 14-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; ADCS-ADL-MCI = modified version of the Alzheimer’s Disease Consortium Study Activities of Daily Living inventory for a mild cognitive impairment population; LS = least squares; Modified iADRS = integrated Alzheimer’s Disease Rating Scale calculated using the ADAS-Cog14 and the ADCS-ADL-MCI. *=p<.05.>