ABSTRACT
Introduction: Preclinical Alzheimer’s disease (AD) is characterized by amyloid-related cognitive decline. Reduction in this decline is used to determine the efficacy of drug therapies designed to forestall the disease in preclinical AD clinical trials, measured by a Preclinical Alzheimer’s Cognitive Composite (PACC). Most studies estimate rates of cognitive change by comparing cognitively normal (CN) older adults with abnormally high beta-amyloid (Aβ+) to those with low levels (Aβ–). However, participants of preclinical AD clinical trials must be Aβ+ for entry. Therefore, we estimated the effect of very high amyloid (Aβ++) and Aβ+ on cognitive change over three years measured by different versions of the PACC in individuals with preclinical AD.
Method: CN older adults underwent Aβ neuroimaging and neuropsychological assessments over three years as part of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Three cognitive composite scores were computed: the Alzheimer’s Disease Cooperative Study (ADCS)–PACC, the ADCS–PACC with no Mini-Mental State Examination (MMSE), and the z-scores of Attention, Verbal Fluency and Episodic Memory for Nondemented Older Adults (ZAVEN) composite.
Results: Compared to the Aβ++ group, the Aβ+ group showed a slower rate of cognitive decline with the largest magnitude of difference reflected by the ADCS–PACC (d = 0.85). The ADCS–PACC excluding the MMSE and the ZAVEN also reflected a moderate to large magnitude of difference between groups (d = 0.62, d = 0.72, respectively).
Conclusions: When all individuals have abnormal Aβ, the level of Aβ at baseline is associated with the rate of subsequent decline. The ADCS–PACC was the most sensitive composite score in showing that lower Aβ is associated with a slower rate of cognitive decline; however, there are limitations to the use of the MMSE. These results provide a benchmark of comparison for preclinical AD clinical trials aiming to slow cognitive deterioration.
Acknowledgments
Alzheimer’s Australia (Victoria and Western Australia) assisted with promotion of the study and the screening of telephone calls from volunteers. The AIBL team wishes to thank the clinicians who referred patients with AD to the study: Brian Chambers, Edmond Chiu, Roger Clarnette, David Darby, Mary Davison, John Drago, Peter Drysdale, Jacqueline Gilbert, Kwang Lim, Nicola Lautenschlager, Dina LoGiudice, Peter McCardle, Steve McFarlane, Alastair Mander, John Merory, Daniel O’Connor, Ron Scholes, Mathew Samuel, Darshan Trivedi, and Michael Woodward. We thank all those who participated in the study for their commitment and dedication to helping advance research into the early detection and causation of AD.
Disclosure statement
C.L.M. is an advisor to Prana Biotechnology Ltd and a consultant to Eli Lilly. P.J.S. is a scientific consultant to Cogstate Ltd. P.M. is a full-time employee of Cogstate Ltd. D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, and Pfizer Inc. V.L.V. served as a consultant for Bayer Pharma.