IMPORTANCE Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS. OBJECTIVE To investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS. DESIGN, SETTINGS, AND PARTICIPANTS In this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities. EXPOSURE APOE status (ε4 carrier vs ε4 noncarrier). MAIN OUTCOMES AND MEASURES For the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately. RESULTS The child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (η p 2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (η p 2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = −4.58 [95% CI, −6.67 to −2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, −1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages. CONCLUSIONS AND RELEVANCE APOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported (continued) Key Points Question What are the associations between the Alzheimer disease risk allele apolipoprotein E (APOE) ε4 and attention across the life span of individuals with Down syndrome? Findings In a cross-sectional study including 80 young children and 240 adults with Down syndrome, an advantage was observed in attention for ε4 carriers relative to ε4 noncarriers among young children. Among young adults, no attentional advantage was observed in ε4 carriers, and possession of an ε4 ...