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Original Investigation
April 2018

Association of β-Amyloid and Apolipoprotein E ε4 With Memory Decline in Preclinical Alzheimer Disease

Author Affiliations
  • 1The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
  • 2CogState, Ltd, Melbourne, Victoria, Australia
  • 3Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
  • 4Centre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, Joondalup, Western Australia, Australia
  • 5Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, Perth, Western Australia, Australia
  • 6Cooperative Research Centre for Mental Health, Carlton, Victoria, Australia
  • 7Commonwealth Scientific and Industrial Research Organisation Preventative Health National Research Flagship, Australian e-Health Research Centre, Brisbane, Queensland, Australia
  • 8Academic Unit for Psychiatry of Old Age, St Vincent’s Health, University of Melbourne, Kew, Victoria, Australia
  • 9National Ageing Research Institute, Parkville, Victoria, Australia
  • 10Department of Nuclear Medicine and Centre for PET (Positron Emission Tomography), Austin Health, Heidelberg, Victoria, Australia
  • 11Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia
JAMA Neurol. 2018;75(4):488-494. doi:10.1001/jamaneurol.2017.4325
Key Points

Question  What is the association of β-amyloid and the presence of the apolipoprotein E (APOE) ε4 with memory decline with increasing age?

Findings  In this longitudinal study of 447 cognitively healthy older adults, memory decline in β-amyloid–positive ɛ4 carriers began earlier (64.5 years of age) than in β-amyloid–positive ɛ4 noncarriers (76.5 years of age). The rate of decline was also faster, such that by 85 years of age, β-amyloid–positive ε4 carriers performed worse than β-amyloid–positive ε4 noncarriers.

Meaning  These results suggest that memory decline in β-amyloid–positive adults may accelerate with older age and that this increase in acceleration may be associated with the APOE ε4 allele.


Importance  Older age, high levels of β-amyloid (Aβ), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aβ, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aβ-positive ε4 carriers and noncarriers has not been determined.

Objective  To determine the association of age, Aβ level, and APOE ε4 with memory decline in a large group of cognitively healthy older adults.

Design, Setting, and Participants  This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent Aβ imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable.

Exposures  β-Amyloid imaging using positron emission tomography, genotyping for APOE ɛ4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up.

Main Outcomes and Measures  Episodic memory composite score.

Results  Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each Aβ-ɛ4 group (24 of 51 Aβ-positive ε4 noncarriers [47.1%] ; 35 of 64 Aβ-negative ε4 carriers [54.7%]; 40 of 72 Aβ-positive ε4 carriers [55.6%]; and 145 of 260 Aβ-negative ε4 noncarriers [55.8%]). Adults with Aβ findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for Aβ (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from Aβ-negative ɛ4 noncarriers at an earlier age in Aβ-positive ɛ4 carriers (64.5 years) than in Aβ-positive ɛ4 noncarriers (76.5 years), such that by 85 years of age, Aβ-positive ε4 carriers performed approximately 1.5 SD units worse on the episodic memory composite than Aβ-negative ε4 noncarriers and approximately 0.8 SD units worse than Aβ-positive ε4 noncarriers. Memory performance of Aβ-negative ɛ4 carriers did not differ from that of the Aβ-negative ɛ4 noncarriers (estimate [SE], 0.001 [0.001]; t = 0.526; P = .77).

Conclusions and Relevance  Prior work has shown that Aβ and ε4 combine to influence memory decline in nondemented older adults. Results of this study indicate that increasing age may further exacerbate these effects. The estimates provided may be used to determine the risk of memory decline associated with Aβ and ε4 at each age.