Memory precision of object-location binding is unimpaired in APOE ε4-carriers with spatial navigation deficits

Abstract

Research suggests that tests of memory fidelity, feature binding and spatial navigation are promising for early detection of subtle behavioural changes related to Alzheimer's disease. In the absence of longitudinal data, one way of testing the early detection potential of cognitive tasks is through the comparison of individuals at different genetic risk for Alzheimer's dementia. Most studies have done so using samples aged 70 years or older. Here, we tested whether memory fidelity of long-term object-location binding may be a sensitive marker even among cognitively healthy individuals in their mid-60s by comparing participants at low and higher risk based on presence of the ε4-allele of the apolipoprotein gene (n = 26 ε3ε3, n = 20 ε3ε4 carriers). We used a continuous report paradigm in a visual memory task that required participants to recreate the spatial position of objects in a scene. We employed mixture modelling to estimate the two distinct memory processes that underpin the trial-by-trial variation in localization errors: retrieval success which indexes the proportion of trials where participants recalled any information about an object's position and the precision with which participants retrieved this information. Prior work has shown that these memory paradigms that separate retrieval success from precision are capable of detecting subtle differences in mnemonic fidelity even when retrieval success could not. Nonetheless, Bayesian analyses found good evidence that ε3ε4 carriers did not remember fewer object locations [F(1, 42) = 0.450, P = 0.506, BF₀₁ = 3.02], nor was their precision for the spatial position of objects reduced compared to ε3ε3 carriers [F(1, 42) = 0.12, P = 0.726, BF₀₁ = 3.19]. Because the participants in the sample presented here were a subset of a study on apolipoprotein ε4-carrier status and spatial navigation in the Sea Hero Quest game [Coughlan et al., 2019. PNAS, 116(9)], we obtained these data to contrast genetic effects on the two tasks within the same sample (n = 33). Despite the smaller sample size, wayfinding deficits among ε3ε4 carriers could be replicated [F(1, 33) = 5.60, P = 0.024, BF₁₀ = 3.44]. Object-location memory metrics and spatial navigation scores were not correlated (all r < 0.25, P > 0.1, 0 < BF₁₀ < 3). These findings show spared object-location binding in the presence of a detrimental apolipoprotein ε4 effect on spatial navigation. This suggests that the sensitivity of memory fidelity and binding tasks may not extend to individuals with one ε4-allele in their early to mid-60s. The results provide further support to prior proposals that spatial navigation may be a sensitive marker for the earliest cognitive changes in Alzheimer's disease, even before episodic memory.

Keywords: APOE; Alzheimer’s disease; early detection; memory; spatial navigation.

Graphical Abstract

Figure 1

Schematic of the precision memory task.

Figure 2

Tested models and results from the mixture modelling approach. (A) Proposed models to capture location memory performance. In Model 1, all object locations are assumed to be correctly recalled without any guess responses (probability of guessing: pU=0). The mean distance of responses from the target can be represented by the width of the von Mises (circular Gaussian) distribution, expressing the precision of memory recall [expressed as the standard deviation (SD) of the von Mises distribution where higher values reflect lower precision; for a more intuitive interpretation where higher values reflect better performance, the SD value can be converted to the von Mises distribution concentration parameter kappa, denoted K; see Supplementary Material]. Model 2 assumes a mixture of guessed and correctly remembered responses, where the proportion of responses that fall within the uniform distribution is denoted by the parameter pU that captures the proportion of guessed responses. For a more intuitive understanding where higher values reflect higher performance this parameter can also be expressed as retrieval success denoted by pT. This parameter captures the proportion of trials within the von Mises distribution, i.e. trials in which the target location was correctly recalled. Model 3 assumes that responses reflect a combination of guessing, correctly remembered responses with variable degree of precision, and swaps of target and distractor locations, represented as von Mises distributions centered at the locations of distractor objects. (B) Distribution of location errors by ε4-status in native circular space (left hand side) and the Standard Mixture Model (von Mises + uniform) fit to responses. Model 2 was identified as the best fitting model in a model comparison procedure detailed in the Supplementary Material.

Figure 3

Precision memory and spatial navigation performance by APOE genotype. (A) Distribution of standardized group differences derived from 1000 permutations where n = 26 subjects were randomly assigned to one sample and n = 20 subjects to another (to match the actual group sizes in our sample). Retrieval success and precision were obtained using mixture modelling on all trials across subjects for the ε3ε3 and the ε3ε4 group, respectively. The red dots represent the standardized true differences in model metrics calculated by subtracting the scores of the ε3ε4 from those of the ε3ε3 group (for guessing, pU: z = 0.31; for precision, SD: z = −0.5). (B) Mean ± standard deviation of identification accuracy, retrieval success and precision for each APOE group. Retrieval success refers to the proportion of trials falling within 63° of the target object. Precision reflects the standard deviation in response-to-target distance for all trials within 63° of the target object. The APOE effect on memory scores and spatial navigation is assessed using general linear models and Bayesian analysis. (C) Mean ± standard deviation of wayfinding distance in the Sea Hero Quest game (Coughlan et al., 2019). *P < 0.05