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.
Highlights
Group differences based on memory metrics derived from modelling across subjects by APOE group
We tested whether the precision of longterm memory for object-location binding is affected in healthy middle- and older-aged apolipoprotein e4-carriers who do not exhibit impairments on standard neuropsychological tests
We used a continuous report paradigm in which participants were asked to recreate object locations as precisely as possible[67] and employed Bayesian mixture modelling to separate memory retrieval success from the precision of retrieved locations.[75,78]
Summary
Alzheimer’s disease has a long preclinical phase during which pathological neural changes occur without overt, detrimental effects on behaviour.[1,2,3,4] This long preclinical phase offers the possibility of interventions that may target further pathological changes and prevent irreversible cell death.[5,6] Cognitive tests are the most cost-effective and simple way to screen for cognitive impairment related to dementia, yet standard neuropsychological tests typically fail to detect these subtle preclinical symptoms of Alzheimer’s disease pathology.[7,8] In the absence of longitudinal data, individuals with high risk for late-onset Alzheimer’s disease based on the e4-allele of the apolipoprotein (APOE) gene are a good model to test the diagnostic sensitivity of cognitive tests because they are more likely than e3e3 carriers to develop the disease, exhibit Alzheimer’s disease pathology at an earlier point in time and decline at a more rapid rate.[9,10,11,12,13,14,15] E4-carriers exhibit deficits in tests of long-term feature binding, mnemonic fidelity and spatial navigation, making these tasks promising markers of incipient cognitive decline related to Alzheimer’s disease.[16,17,18] Yet, there are few studies testing these tasks in neuropsychologically unimpaired middleaged e4-carriers, and even fewer studies looked at more than one of these different types of tasks in the same sample. We determined whether a novel test of long-term object-location binding is sensitive to APOE effects in a sample with e3e4 carriers who previously exhibited spatial navigation deficits.[19]
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