Spatial pattern separation deficits in early Alzheimer’s disease are comparable in humans and animal models

Spatial pattern separation (SPS) is a memory process that enables the discrimination of similar spatial locations. This process is vulnerable to pathophysiological changes in the early stages of Alzheimer's disease (AD), but the translational potential of its testing remains unclear. This study aimed to evaluate the potential of SPS testing as a translational cognitive marker for identifying early AD and enabling direct comparisons of cognitive outcomes in animals and humans. We used a validated SPS task to examine biomarker-defined participants with amnestic mild cognitive impairment due to AD (AD aMCI; n = 56) and cognitively normal (CN) participants (n = 60). An animal version of this task, based on a modified Morris Water Maze task, was used to test six-month-old transgenic TgF344-AD rats (n = 38) and wild-type (WT) rats (n = 36). AD aMCI participants performed worse than CN participants, with performance declining as distance decreased. These results remained unchanged when adjusted for memory performance. TgF344-AD rats performed worse than WT rats in a probe trial with a 90° SPS design, but not in probe trials with an 180° SPS design or no SPS demands. The discriminatory power of the task was similar in the human and animal experiments. The findings demonstrate comparable SPS deficits in the early stages of AD in both humans and rodent models, which are not attributable to general memory impairment. SPS testing enables direct comparisons to be made between the cognitive performance of rats and humans, making it a promising approach for translational AD research.