Brain dynamics during mnemonic discrimination in preclinical and prodromal Alzheimer’s disease

Abstract

AbstractBackgroundMnemonic discrimination of similar lures and targets is emerging as a promising marker of subtle memory decline in early Alzheimer’s disease (AD) due to its reliance on regions most affected by AD pathology. Tau pathology initially targets medial temporal lobe (MTL) regions in an anterior‐temporal (AT) brain network, which is preferentially involved in object processing, before it can be found in the posterior‐medial (PM) network associated with scene processing. Tests of object and scene mnemonic discrimination may therefore serve as behavioural indicators of the functional integrity of AT and PM regions, respectively. We investigated behavioural and neural changes in mnemonic discrimination across the AD spectrum.Method201 DELCODE cohort participants underwent fMRI scanning during an object‐scene mnemonic discrimination task at four time points from baseline to three‐year follow‐up. At baseline, participants were split by diagnostic group (cognitively unimpaired = CU, subjective cognitive decline = SCD, mild cognitive impairment = MCI, dementia of the Alzheimer’s type = DAT; Table 1). We identified brain regions showing lower activity to repeated targets but not similar lures, indicative of successful pattern separation of overlapping memory representations.ResultThese findings present cross‐sectional baseline data. Behavioural data showed a main effect of group but no group by category (objects, scenes) interaction. CUs and SCDs outperformed patients across domains and CUs scored higher than SCDs only in scene discrimination. Amyloid positive and negative CUs and SCDs did not differ in performance. Successful mnemonic discrimination engaged hippocampus, parahippocampal cortex, precuneus, angular gyrus, and inferior frontal regions for both objects and scenes. Correct object discrimination was additionally associated with amygdala and transentorhinal cortical activity. Reduced brain activation in regions of the anterior‐temporal and posterior‐medial network during successful object and scene mnemonic discrimination, respectively, was found in patient groups (MCI+DAT) compared to cognitively normal (CU+SCD) older adults.ConclusionOur findings lend further support to the utility of mnemonic discrimination as indicator of memory impairment in early AD. Object and scene tasks engage partially dissociable brain networks and individuals with cognitive impairment show reduced neural pattern separation effects. These findings lay the groundwork for future longitudinal analyses to track these changes based on clinical and biomarker status.