The association between apolipoprotein E genotype, plasma level, and cognition in a non-demented cohort

In a majority of studies, the apolipoprotein E-ϵ4 allele (apoE-ϵ4) has been shown to be a significant risk factor for Alzheimer's disease (AD). However, the nature of the association between apoE-ϵ4 and cognition in non-demented persons remains unresolved. Some studies have demonstrated that apoE-ϵ4 positive individuals perform significantly worse on neuropsychological tests compared to non-apoE-ϵ4 individuals, while other studies have reported that apoE-ϵ4 is not associated with cognitive impairment in normal aging. Neurobiological studies using animal and human tissue samples suggest that apoE isoforms and protein levels may affect neuronal growth/plasticity and the accumulation of neuropathological changes of the type seen in AD. However, the association between apoE plasma levels and cognition within apoE genotype groups has largely been unexplored. In this study, 1474 non-demented participants from the Framingham Study offspring cohort (mean age = 62.1, SD = 9.5, range = 36–88) were administered a neuropsychological test battery. Participants were divided by apoE genotype: 207 apoE-ϵ2 (ϵ2/ϵ2, ϵ2/ϵ3), 962 apoE-ϵ3 (ϵ3/ϵ3), and 305 apoE-ϵ4 (ϵ4/ϵ4, ϵ3/ϵ4), sex, and age (<70 and ≥70). Participants were also divided by the presence or absence of the apoE-ϵ4 allele. For a subset of these individuals (n = 1145), apoE plasma levels were also obtained. Results revealed that the apoE-ϵ4 group performed significantly worse than the apoE-ϵ3 and apoE-ϵ2 groups on tests of verbal short-term memory and attention, despite the fact that pre-morbid intellectual function was superior in the apoE-ϵ4 group. When examining apoE plasma levels, results showed that high apoE plasma level in apoE-ϵ4 participants was associated with poorer cognitive performance. A statistically non-significant trend of better cognitive performance with elevated apoE plasma level was evidenced in apoE-ϵ3 individuals. These findings suggest that apoE-ϵ4 affects cognition in non-demented persons. This effect was more robust in females than males. Results also demonstrate that apoE plasma levels may influence cognition differently in apoE-ϵ3 and apoE-ϵ4 individuals.