Clinically normal elderly adults at genetic risk for sporadic Alzheimer’s disease have a path integration deficit

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is associated with cognitive impairment, including spatial disorientation. Disorientation may be an early indicator of AD because spatial navigation relies on entorhinal cortex, the first cortical region affected by AD pathology. To test the hypothesis that spatial navigation declines in preclinical AD, we investigated age and genotype effects on a virtual path integration task, the "Apple Game" (Bierbrauer et al. 2020).MethodParticipants navigated in a virtual field and had to drop a basket to their initial location. Difficulty varied according to two parameters: (1) the number of interim locations (distractor) participants had to visit (0, 1, or 2); and (2) the presence or absence of a landmark. We recruited 145 clinically normal participants (MMSE>24/30, median age= 64). We genotyped the apolipoproteinE (APOE) gene, the ε4 allele of which is a risk factor for AD. We classified participants as E4 (n=41) if they had at least one ε4 allele and E3 (n=104) otherwise (table 1). We used linear mixed models to predict the drop error, i.e., the Euclidean distance between the correct and the actual drop location. The two components of the drop error, the angle and distance errors, were analyzed.ResultsThe drop error increased with age. In trials with no distractor and no landmark, we observed higher drop error for E4 than E3 participants older than 70 years (fig.1), suggesting a deficit in pure path integration for oldest E4 carriers. This deficit was due to higher angle error (fig.2) rather than distance error (fig.3). In trials with distractors, performance dropped to chance level for all participants above 50 years (fig.4), suggesting the task was too difficult in general. In trials with landmark, the error was not influenced by the APOE genotype.ConclusionThis spatial navigation task detected a deficit in pure path integration in elderly E4 carriers, when the task was not too difficult. The deficit may reflect an impairment in grid cells localized in the entorhinal cortex. Indeed, this group has probably the most AD neuropathology brain deposit. By contrast, landmark‐based navigation was impaired with age but not related to AD risk.