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

IMPORTANCE Older age, high levels of beta-amyloid (A beta), and the presence of the apolipoprotein E (APOE) epsilon 4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, A beta, and epsilon 4 are associated with memory decline remains unclear, and the age at which memory decline begins for A beta-positive epsilon 4 carriers and noncarriers has not been determined. OBJECTIVE To determine the association of age, A beta level, and APOE epsilon 4 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 A beta 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 beta-Amyloid imaging using positron emission tomography, genotyping for APOE epsilon 4, 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 A beta-epsilon 4 group (24 of 51 A beta-positive epsilon 4 noncarriers [47.1%]; 35 of 64 A beta-negative epsilon 4 carriers [54.7%]; 40 of 72 A beta-positive epsilon 4 carriers [55.6%]; and 145 of 260 A beta-negative epsilon 4 noncarriers [55.8%]). Adults with A beta findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for A beta (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from A beta-negative epsilon 4 noncarriers at an earlier age in A beta-positive epsilon 4 carriers (64.5 years) than in A beta-positive epsilon 4 noncarriers (76.5 years), such that by 85 years of age, A beta-positive e4 carriers performed approximately 1.5 SD units worse on the episodic memory composite than A beta-negative epsilon 4 noncarriers and approximately 0.8 SD units worse than A beta-positive epsilon 4 noncarriers. Memory performance of A beta-negative e4 carriers did not differ from that of the A beta-negative epsilon 4 noncarriers (estimate [SE], 0.001 [0.001]; t = 0.526; P = .77). CONCLUSIONS AND RELEVANCE Prior work has shown that A beta and epsilon 4 combine to influence memory decline in nondemented older adults. Results of this study indicate that increasing agemay further exacerbate these effects. The estimates provided may be used to determine the risk of memory decline associated with A beta and epsilon 4 at each age.