Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults

Article type: Research Article

Authors: Dang, Christa^{a; b; *} | Harrington, Karra D.^{b; c} | Lim, Yen Ying^b | Ames, David^{d; e} | Hassenstab, Jason^{f; g; h} | Laws, Simon M.^{c; i; j} | Yassi, Nawaf^{b; k} | Hickey, Martha^a | Rainey-Smith, Stephanie^{l; m} | Robertson, Joanne^b | Sohrabi, Hamid R.^{l; p} | Salvado, Olivier^q | Weinborn, Michael^{l; m; r} | Villemagne, Victor L.^{b; n; o} | Rowe, Christopher C.^{n; o} | Masters, Colin L.^b | Maruff, Paul^{b; s} | for the AIBL Research Group^t

Affiliations: [a] Department of Obstetrics and Gynaecology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia | [b] The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia | [c] Cooperative Research Centre for Mental Health, Parkville, VIC, Australia | [d] Department of Psychiatry, Academic Unit for Psychiatry of Old Age, The University of Melbourne, Parkville, VIC, Australia | [e] National Ageing Research Institute, Parkville, VIC, Australia | [f] Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA | [g] Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA | [h] Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, USA | [i] Collaborative Genomics Group, Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia | [j] School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Western Australia, Australia | [k] Department of Medicine and Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia | [l] Centre of Excellence for Alzheimer’s Disease Research and Care, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia | [m] Australian Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia | [n] Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia | [o] Department of Medicine, Austin Health, The University of Melbourne, Melbourne, VIC, Australia | [p] School of Psychiatry and Clinical Neurosciences, University of WA, Nedlands, Western Australia, Australia | [q] CSIRO Health and Biosecurity, the Australian eHealth Research Centre, Brisbane, QLD, Australia | [r] School of Psychological Science, University of Western Australia, Crawley, WA, Australia | [s] CogState Ltd., Melbourne, VIC, Australia | [t] https://aibl.csiro.au

Correspondence: [*] Correspondence to: Christa Dang, The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville VIC 3052, Australia. Tel.: +61 3 9035 3000; Fax: +61 3 9035 3107; E-mail: [email protected].

Abstract: Background:Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. Objective:To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods:Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOE ɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. Results:17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOE ɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion:Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Keywords: Alzheimer’s disease, APOE ɛ4, biomarkers, dementia, mild cognitive impairment

DOI: 10.3233/JAD-180507

Journal: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1313-1325, 2018