Neuropsychologia 46 (2008) 1688–1697 A deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease V.L. Villemagne a,b,c,d,∗ , K.E. Pike a,e , D. Darby d,f , P. Maruff d,f , G. Savage e,1 , S. Ng a , U. Ackermann a , T.F. Cowie c , J. Currie g , S.G. Chan a , G. Jones a , H. Tochon-Danguy a , G. O’Keefe a , C.L. Masters b,c,d , C.C. Rowe a,h a Department of Nuclear Medicine, Centre for PET, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia b The Mental Health Research Institute of Victoria, Parkville, VIC, Australia c Department of Pathology, University of Melbourne, VIC, Australia d Centre for Neuroscience, University of Melbourne, VIC, Australia e School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, VIC, Australia f Cogstate Pty Ltd., Melbourne, VIC, Australia g St Vincent’s Hospital, Melbourne, VIC, Australia h Department of Medicine, (Austin Health) University of Melbourne, VIC, Australia Received 29 July 2007; received in revised form 28 December 2007; accepted 1 February 2008 Available online 14 February 2008 Abstract Approximately 30% of healthy persons aged over 75 years show A deposition at autopsy. It is postulated that this represents preclinical Alzheimer’s disease (AD). We evaluated the relationship between A burden as assessed by PiB PET and cognitive decline in a well-characterized, non-demented, elderly cohort. PiB PET studies and cognitive tests were performed on 34 elderly participants (age 73 ± 6) from the longitudinal Melbourne Healthy Aging Study (MHAS). Subjects were classified as being cognitively ‘stable’ or ‘declining’ by an independent behavioural neurologist based on clinical assessment and serial word-list recall scores from the preceding 6–10 years. Decline was calculated from the slope of the word-list recall scores. A burden was quantified using Standardized Uptake Value normalized to cerebellar cortex. Ten subjects were clinically classified as declining. At the time of the PET scans, three of the declining subjects had mild cognitive impairment, one had AD, and six were declining but remained within the normal range for age on cognitive tests. Declining subjects were much more likely to show cortical PiB binding than stable subjects (70% vs. 17%, respectively). Neocortical A burden correlated with word-list recall slopes (r = -0.78) and memory function (r = -0.85) in the declining group. No correlations were observed in the stable group. A burden correlated with incident memory impairment and the rate of memory decline in the non-demented ageing population. These obser- vations suggest that neither memory decline nor A deposition are part of normal ageing and likely represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis. © 2008 Elsevier Ltd. All rights reserved. Keywords: Brain imaging; Mild cognitive impairment; Amyloid; Normal ageing; PiB; Positron emission tomography ∗ Corresponding author at: Department of Nuclear Medicine, Centre for PET, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia. Tel.: +61 3 9496 3321; fax: +61 3 9458 5023. E-mail address: villemagne@petnm.unimelb.edu.au (V.L. Villemagne). 1 Present address: Macquarie Centre for Cognitive Science (MACCS), Mac- quarie University, Sydney, NSW, Australia. 1. Introduction Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is an irreversible, progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline, leading invariably to death (Masters, Cappai, Barnham, & Villemagne, 2006). The progressive nature of neurodegener- ation suggests an age-dependent process that ultimately leads to synaptic failure and neuronal damage in cortical areas of 0028-3932/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2008.02.008