Association Between Apolipoprotein E ε2 vs ε4, Age, and β-Amyloid in Adults Without Cognitive Impairment.

Importance Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E e4 (APOE e4) in Alzheimer disease and the ease of identifying e4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation. Objective To determine whether the e2 allele is protective against Aβ accumulation in the presence of the e4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction. Design, setting, and participants This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded. Main outcomes and measures Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite. Results A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE e2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], e24, 1.11 [95% CI, 1.08-1.14]; e34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of e4, with Aβ levels in the APOE e24 group (n = 115; e24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE e34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE e4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between e4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78). Conclusions and relevance These findings suggest that the protective outcome of carrying an e2 allele in the presence of an e4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the e2 allele in order to facilitate Aβ clearance in e4 carriers. Such a treatment strategy is appealing, as e4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many e4 carriers begin to accumulate Aβ in early middle age.