Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome

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 allele was associated with a disadvantage among older adults. Meaning Although APOE ε4 is a risk allele for Alzheimer disease later in life, it may be associated with an attentional advantage in the early development of individuals with Down syndrome.


eMethods 1. Participants
Out of 115 young children with Down syndrome (DS) recruited via existing participant databases and support groups (see 1 ), 104 attended the lab session and 98 performed an attentional eye-tracking task. Insufficient data quality (see eMethods 2 in the Supplement) led to the exclusion of 14 children, and genetic data were not available for three children. Of the remaining 81 children, one child carried genotype APOE ε2/ε4, which has an unclear association with AD risk, and was excluded from further analyses. The final sample therefore consisted of 80 children aged between 8 and 62 months. Twenty-three children (28.8%) were ε4 carriers and 57 (71.3%) were ε4 noncarriers, which reflects the distribution in the typically developing population. 2 The APOE groups did not differ in key participant characteristics (Table).
The adult group consisted of 452 participants with DS, recruited through similar channels as the children group (see 1,3 ). Genetic and attentional data of interest were available for 243 individuals. Three participants carried APOE ε2/ε4 and were excluded from any further analysis. The final sample of 240 participants consisted of adults aged between 16 and 71 years, with 61 (25.4%) ε4 carriers and 179 (74.6%) ε4 noncarriers. This is similar to the child group and the typically developing population. 2 Again, the APOE groups did not differ in key participant characteristics (Table). eMethods 2. The Gap-Overlap Task This gaze-contingent task was a part of a larger battery of tasks and was adopted from the British Autism Study of Infant Siblings (BASIS). It has previously been successfully used with young children with DS. 4 The task was administered using a Tobii TX300 eye-tracking system (Tobii AB, Stockholm, Sweden). The participants were seated in front of a 23-inch liquid-crystal display (LCD) monitor at a distance of around 65cm. A webcam was used to monitor behaviour, and sessions were video recorded for analytic reference. Stimulus presentation and data collection were performed using the Task Engine (https://sites.google.com/site/taskenginedoc/) framework for Matlab (MathWorks, Inc., Natick, Massachusetts, United States).
An automatic five-point calibration was run wherein coloured spirals expanded and contracted in each of the four corners and in the centre of the screen. Following this brief five-point calibration, participants completed the gap-overlap task (adapted from 5,6 ). In this task, participants were presented with a gazecontingent central stimulus (CS; i.e., a dynamic colourful clock) and, subsequently, a peripheral stimulus (PS; i.e., a white cloud) which appeared randomly either to the right or left of the CS at an eccentricity of 19°. The CS initially loomed on screen until the participant fixated on it, at which point it span for a random 600-700ms in order to ensure attentional engagement before the onset of the PS. When the participant fixated upon the PS, or 1200ms after PS onset (whichever was sooner), the reward stimulus was presented. This took the form of various cartoon characters at the location of the PS which span or shrank whilst emitting various child-friendly sounds. Saccadic reaction times (SRTs) were calculated as the latency in ms to disengage from the CS and saccade to the PS.
Attentional abilities were probed in three conditions which manipulated the timing of the offset of the CS. In the baseline condition, CS offset occurred at the same time as PS onset. In the gap condition, CS offset preceded PS onset by 200ms. In the overlap condition, the CS remained on screen at PS onset and for the duration of PS presentation. Trials were presented in blocks of 12, until 12 valid trials per condition were acquired or a maximum of 60 trials were presented. Trials were considered valid if the following conditions were met: (1) gaze fell on the CS; (2) no gaps of missing data longer than 200ms were present during the CS period (before PS onset); (3) there was at least one sample of gaze at the CS area of interest within 50ms either side of PS onset; (4) no gaps of missing data longer than 100ms were present during the PS period (between PS onset and reward onset); (5) SRT was longer than 150ms and shorter than 1200ms; (6) gaze did not go in the opposite direction to the side of the PS; (7) gaze did not enter the PS area of interest (AOI) after engagement with the CS but before PS onset. Trials that failed any of the above criteria were invalidated and removed from further analysis. Mean SRTs were calculated for each condition separately, using only valid trials. Participants with fewer than six valid trials per condition were removed entirely from the analysis. For the purpose of the current research question, two conditions of this task were of interest for the analysis: gap and overlap. The gap effect was computed by subtracting gap SRT from overlap SRT. 7 eMethods 3. CANTAB Simple Reaction Time Task For this task there was a variable stimulus onset asynchrony (SOA) of between 750ms and 1500ms and a preempt delay of 100ms in which any response was regarded as 'too early'. Following the pre-empt delay, participants had 3000ms to respond to each trial. Participants completed an initial practice block of 24 trials, followed by two test blocks of 50 trials each. The standard deviation (SD) of response times for these two test blocks was used as the outcome for this task.

eResults. Impact of Intellectual Disability on Simple Reaction Time Latency Standard Deviation
To examine the added influence of level of intellectual disability on this relationship, we added this variable to the regression model with an APOE group*level of intellectual disability interaction to further examine the results found in the adult group. This regression model was significant , F(8,231) [-76.51, 6.71]), p=.123) were not associated with performance. This model with intellectual disability was a better fit of the data (p<.001). These results show that APOE ε4 status is associated with attentional abilities as people age, even when adjusting for the impact of intellectual disability.