AbstractBackgroundHyperlipidemia is associated with increased risk of Alzheimer’s disease and related dementias (ADRD). Apolipoprotein E (APOE) plays a key role in lipid transport and is regulated by APOE. APOEe4 carriage may increase ADRD risk by altering lipid metabolism in the brain. We sought to understand the relationship between total cholesterol and memory when moderated by APOEe4 carriage hypothesizing that the negative effects of elevated total cholesterol on memory would be strongest among APOEe4 carriers.MethodParticipant data were extracted from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐1) database. Total cholesterol and APOEe4 carriage were measured from blood samples collected at baseline. Rey Auditory Verbal Learning Test (RAVLT) measured delayed recall and recognition normed using the Mayo’s Older Americans Normative Studies (MOANS). We used multiple regression to examine the relationship between total cholesterol, APOEe4, and cognition, controlling for age, gender, and education. Total cholesterol by APOEe4 carriage interactions were tested using a p<0.1.ResultAmong 1776 participants, 55% (n = 978) were male and average age was 74 (SD = 7). APOEe4 non‐carriers had a mean total cholesterol of 192 (SD = 40) mg/dL compared to 197 (SD = 40) among APOEe4 heterozygotes and 200 (SD = 42) among APOEe4 homozygotes (Table 1). Higher total cholesterol was associated with better delayed recall performance (β = 0.01, p = .01). There was a significant interaction (β = ‐0.01, p = .07) such that higher total cholesterol among APOEe4 non‐carriers was associated with better delayed recall (β = 0.01) whereas higher total cholesterol among APOEe4 homozygotes was associated with worse delayed recall (β = ‐0.004) (Figure 1). When modeling recognition, there was no main effect of total cholesterol; however, there was a significant interaction between total cholesterol and APOEe4 (β = ‐0.01, p = .09). This interaction showed a positive relationship between total cholesterol and recognition in APOEe4 non‐carriers (β = 0.003) but a negative relationship in APOEe4 homozygotes (β = ‐0.01) (Figure 1).ConclusionCompared to non‐carriers, APOEe4 carriers, particularly homozygotes, may be especially sensitive to the deleterious effects of elevated total cholesterol on memory performance. This study adds to the extant literature demonstrating an effect of APOEe4 allele on the relationship between cholesterol and cognition.