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

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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.


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.


β-Amyloid imaging using positron emission tomography, genotyping for APOE [Latin Small Letter Open E]4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up.

Main Outcomes and Measures

Episodic memory composite score.


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-[Latin Small Letter Open E]4 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 [Latin Small Letter Open E]4 noncarriers at an earlier age in Aβ-positive [Latin Small Letter Open E]4 carriers (64.5 years) than in Aβ-positive [Latin Small Letter Open E]4 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 [Latin Small Letter Open E]4 carriers did not differ from that of the Aβ-negative [Latin Small Letter Open E]4 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.

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