Possible positive effect of the APOE ε2 allele on cognition in early to mid-adult life

Abstract

Background: ε4 allele possession is associated with an increased risk of Alzheimer's disease. Its effects earlier in life are less well understood. Previous studies have reported both detrimental effects and a lack of effect on cognition outside dementia. We used genotype based recall from the ALSPAC study to investigate whether APOE genotype influences cognition in earlier adult life.

Methods: We invited all individuals with the rarer ε22 or ε44 genotypes and equal numbers of those with ε32, ε33 or ε34 APOE genotypes (total n invited = 1936, ages 23-67). Participants were screened for dementia using the Addenbrooke's Cognitive Examination Revised (ACE-R). Participants were asked to complete a 3 h battery of neuropsychological tests covering a range of cognitive domains. The primary outcome was performance on the Rey Auditory Verbal Learning Test (RAVLT). Transformation of variables was used where required to permit parametric testing. As genotypes are unlikely to be confounded unadjusted analyses were performed.

Results: 114 participants were recruited to the study (39 ε33, 27 ε34, 15 ε44, 26 ε32 & 7 ε22). ε4+ participants had higher scores on the cognitive failures questionnaire (10 point increase, p = 0.006) but no deficits on objective cognitive testing. ε2 carriers had slightly better episodic memory performance (p = 0.016), slightly improved n-back accuracy and better executive functioning (trails A&B, p = 0.005).

Conclusions: It is intriguing that the ε2+ group performed better as this group have a lower risk of Alzheimer's disease. Most previous studies have analysed as ε4/non ε4 so may have missed this effect.

Keywords: ALSPAC; Apolipoprotein E; Cognition; Executive functioning; Genetics; Memory episodic.

Fig. 1

The flow of potential participants through the study.

Fig. 2

Results from the RAVLT. There was evidence that the ε2+ group remembered more words in trials I-V (A) but no statistical evidence to support a between group difference at the long delay time point (B). The standard deviations for each group are shown in the error bars. A post hoc Dunn’s test suggested that the ε2+ group remembered more words than either the ε33 group (p = 0.011) or the ε4+ group (p = 0.012). ^* denotes p < 0.05.

Fig. 3

Episodic list learning. The standard deviations for each group are shown in the error bars. There was evidence from a post-hoc Dunn’s test that the ε2+ group performed better than the ε33 (p = 0.016) group and the e4+ group (p = 0.007). ^* denotes p < 0.05.

Fig. 4

The results shown are the time taken to complete the trails B task minus the time taken to complete the trails A task. Standard deviations for each group are shown in the error bars. There was evidence from a post-hoc Dunn’s test that the ε2+ group performed better than the ε33 (p = 0.005) group and the ε4+ group (p < 0.001). ^* denotes p < 0.05 and ^** denotes p < 0.01.

Fig. 5

Results from the CFQ (A). Standard deviations for each group are shown in the error bars. There was evidence from a post-hoc Dunn’s test that the ε4+ group had higher scores than the ε33 (p = 0.021) group and the ε2+ group (p = 0.015). As shown in figure B the ε4+ group had higher scores on the DASS. ^* denotes p < 0.05.