Visual Memory Deficits in Middle-Aged APOE ϵ4 Homozygotes Detected Using Unsupervised Cognitive Assessments

Background: The apolipoprotein E (APOE) ϵ4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ϵ4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ϵ4 heterozygotes; 50 ϵ4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ϵ4 heterozygotes; 31 ϵ4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ϵ4 homozygotes compared with ϵ4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ϵ4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ϵ4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ϵ4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ϵ4 homozygosity increases with older age. APOE ϵ4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships.