NMDA Receptor Function during Mnemonic Processing in Patient’s with AD: The Good, The Bad and the Ugly

Alzheimer’s disease (AD) is the most prevalent cause of dementia in older adults, and initially presents with a decline in explicit (recognition) memory. N-methyl-D-aspartate (NMDA) receptors are implicated in AD pathology, given its crucial role in learning and memory but also as a potentially toxic channel whereby NMDA hyperexcitability may exacerbate or initiate neuronal death.
In this study we aimed to examine whether receptor-specific connectivity parameters are predictive of memory dysfunction or disease duration. We analysed EEG data from patients suffering with AD dementia (n=21) and healthy age-matched controls (n=21), during two behavioural tasks. These tasks investigated visual priming and recognition, in which novelty is manipulated, to examine implicit and explicit memory. Behavioural data including reaction times, and a wide selection of demographic data, were also collected. Source localised EEG revealed a visual-temporo-frontal bilateral network of active regions during the recognition phase. Dynamic Causal Models (DCMs) of EEG data from these sources were optimised, whereby receptor-related dynamics were explicitly modelled and fit to each patient’s dataset. Parameters were analysed using Parametric Empirical Bayes (PEB) which aims to test for significant covariation in parameter estimates for group-level covariates.
Consistent with its role in learning and memory, in the temporal lobe, NMDA receptor activation in the left hemisphere was associated with better memory performance in all participants. The PEB analysis also showed, however, that NMDA receptor conductance was increased in right temporal regions, in AD patients compared to controls, and that this increase did not confer any memory benefit.
Our results suggest that synaptic NMDA receptor function while required for memory encoding was hyperexcitable in non-task related pathways in AD patients compared to controls. These results, observed directly for the first time in humans, suggest an imbalance or pervasive NMDA receptor channel function associated with AD pathology.