APOEɛ4 Genotype, Amyloid, and Clinical Disease Progression in Cognitively Normal Older Adults

Article type: Research Article

Authors: Hollands, Simone^{a; *} | Lim, Yen Ying^b | Laws, Simon M.^{c; d; e} | Villemagne, Victor L.^{b; f; g} | Pietrzak, Robert H.^h | Harrington, Karra^b | Porter, Tenielle^{c; d; e} | Snyder, Peterⁱ | Ames, David^{j; k} | Fowler, Christopher^b | Rainey-Smith, Stephanie R.^{c; d} | Martins, Ralph N.^{c; d} | Salvado, Olivier^l | Robertson, Joanne^b | Rowe, Christopher C.^{f; g} | Masters, Colin L.^b | Maruff, Paul^{b; m} | for the AIBL Research Group

Affiliations: [a] La Trobe University, Melbourne, VIC, Australia | [b] The Florey Institute, The University of Melbourne, Parkville, VIC, Australia | [c] Centre of Excellence for Alzheimer’s Disease Research and Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia | [d] Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, WA, Australia | [e] Co-operative Research Centre for Mental Health, http://www.mentalhealthcrc.com | [f] Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia | [g] Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia | [h] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA | [i] Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA | [j] Academic Unit for Psychiatry of Old Age, St. Vincent’s Health, The University of Melbourne, Kew, VIC, Australia | [k] National Ageing Research Institute, Parkville, VIC, Australia | [l] Commonwealth Scientific Industrial Research Organization (CSIRO) Preventative Health National Research Flagship, Australian e-Health Research Centre-BiaMedIA, Brisbane, QLD, Australia | [m] Cogstate Ltd., Melbourne, VIC, Australia

Correspondence: [*] Correspondence to: Simone Hollands, La Trobe University, Melbourne 3086, VIC, Australia. Tel.: +61 3 966 41300; Fax: +61 3 966 41301; E-mail: [email protected].

Abstract: Background: In cognitively normal (CN) older adults, carriage of the apolipoprotein E (APOE) ɛ4 allele is associated with increased risk for dementia of the Alzheimer type (AD-dementia). It is unclear whether this occurs solely through APOE ɛ4 increasing amyloid-β (Aβ) accumulation or through processes independent of Aβ. Objective: To determine the extent and nature to which APOE ɛ4 increases risk for clinical disease progression in CN older adults. Methods: Data from the total (n = 765) and Aβ-imaged (n = 423) CN cohort in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing was analyzed using Cox proportional hazard models to estimate ɛ4 risk for clinical disease progression over a 72-month follow-up. Results: With Aβ status unknown and risk from demographic characteristics controlled, ɛ4 carriage increased risk for clinical disease progression over 72 months by 2.66 times compared to risk of non-ɛ4 carriage. Re-analysis with Aβ status included showed that abnormally high Aβ increased risk for clinical disease progression over 72 months by 2.11 times compared to risk of low Aβ. However, with Aβ level known, ɛ4 carriage was no longer predictive of clinical disease progression. Conclusion: In CN older adults, the risk of ɛ4 for clinical disease progression occurs through the effect of ɛ4 increasing Aβ levels.

Keywords: Alzheimer’s disease, Alzheimer type dementia, amyloid-β, apolipoprotein E4, positron emission tomography

DOI: 10.3233/JAD-161019

Journal: Journal of Alzheimer's Disease, vol. 57, no. 2, pp. 411-422, 2017