Dissociable effects of APOE-ε4 and β-amyloid pathology on visual working memory

Abstract

Although APOE-ε4 carriers are at significantly higher risk of developing Alzheimer's disease than non-carriers¹, controversial evidence suggests that APOE-ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)^2,3. In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of APOE-ε4 and β-amyloid pathology (quantified using ¹⁸F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, APOE-ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall respectively. ε4-carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4-carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer's disease.

Figure 1. Study design: (a) flow-chart of data acquisition and reasons for missing data; (b) presentation of the “What was where?” task; (c) illustration of outcome measures

The 398 cognitively normal participants with complete biomarker data formed the main analysis sample; see Methods and for more details on the definitions of neurological and major psychiatric disorders. * In most cases, this was due to erroneous segmentation of vascular abnormalities such as stroke or demyelination. **These numbers add up to 46 because some participants had more than one condition. (b) and (c) are reprinted from Liang et al. (2016) under the terms of the Creative Commons Attribution License (CC BY) https://creativecommons.org/licenses/by/4.0/. In the middle and right-hand images of (c), green circles indicate the original location of the target object, red circles indicate the original locations of non-target objects, and blue lines indicate measured localisation error. Object identification (c left-hand panel): the participant is required to select the object that they remember seeing. Localisation error (c middle panel) is measured from the location reported by the participant to the location of the closest object; if the reported location is within 140 pixels of the location of a non-target object, this is considered to be a misbinding error. Gross localisation error (c right-hand panel) is measured from the location reported by the participant to the original location of the target object.

Figure 2. Performance on the “What was where?” task in cognitively normal participants (n = 398), by amyloid status and APOE-ε4 (carriers vs. non-carriers): (a) Identification error rate; (b) Localisation error

Figure (a) shows the main effects of amyloid status and APOE-ε4 on identification error rate. Figure (b) shows the main effect of APOE-ε4 on localisation error. Markers show adjusted means from the multivariable regression models, adjusted for delay (long vs. short), load (low vs. high), sex, age at assessment, childhood cognitive ability, education, socioeconomic position, white matter hyperintensity volume, hippocampal volume and total intracranial volume. Error bars show 95% confidence intervals. Note that the plotted values are essentially unchanged if the model does not include adjustment for white matter hyperintensity volume, hippocampal volume and total intracranial volume. In Figure (b), data were log-transformed for analysis but the means and confidence intervals presented here have been back-transformed for ease of interpretation. For numbers of participants in each group, see Supplementary Table 1.

Figure 3. Association between β-amyloid burden (quantified using Standardised Uptake Value Ratio) and localisation error on the “What was where?” task, for APOE-ε4 carriers (n = 120) and non-carriers (n = 278)

Solid lines represent marginal means from the multivariable regression model (see methods) and shaded areas represent 95% confidence intervals, with ε4-carriers shown in red and non-carriers shown in blue. Models were adjusted for load (low vs. high), delay (short vs. long), sex, age, education, socioeconomic position, white matter hyperintensity volume, hippocampal volume, and total intracranial volume, and no adjustments were made for multiple comparisons. Markers show each participant’s mean localisation error across the experiment as a whole. This illustrates the interaction between APOE-ε4 and β-amyloid burden (p=0.043).