Lower synaptic density and higher neurofibrillary tau are associated with worse cognitive performance

Abstract

AbstractBackgroundSynaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). PET radioligands for synaptic vesicle glycoprotein 2A (SV2A) provide an index for synaptic density in the brain. While development of these tracers is a major advance for the field of AD, little is yet known about regional synapse loss in AD or the extent to which synapse loss accounts for cognitive dysfunction in vivo. Here we tested whether regional synaptic density measured with [11C]UCB‐J is associated with cognition. Secondarily, we examined the association between tau, measured using [18F]MK‐6420 PET, and cognitive dysfunction.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study (Table 1). Cognitive functioning was measured using the Preclinical Alzheimer Cognitive Composite (PACC)(Donohue et al, 2014). Neurofibrillary tau in the entorhinal cortex (ERC) was detected using [18F]MK‐6420 SUVR. A global measure of synaptic density was calculated using volume‐averaged DVRs in the medial temporal lobe (hippocampus, entorhinal cortex, parahippocampus, and perirhinal cortex), superior and inferior parietal cortices, and the frontal lobe. Pearson’s correlations assessed the following relationships: PACC : ERC tau, PACC : global synaptic density, and PACC : regional synaptic density.ResultERC tau and PACC score showed a significant inverse relationship: r = ‐0.51, P = 0.004. While global synaptic density and PACC score were not significantly related, when individual regions were tested, hippocampal synaptic density showed a significant positive relationship with the PACC score (P = 0.05) (Figure 1A).ConclusionERC tau PET SUVR was robustly associated with poorer cognitive performance. While synapse loss has been observed among multiple regions in AD, our preliminary results suggest that synapse loss in the hippocampus is most closely associated with cognitive dysfunction. This preliminary work suggests that ERC tau is more strongly associated with Alzheimer’s‐related cognitive decline than global or hippocampal synaptic density in participants who are mostly cognitively unimpaired. Future work will include group comparisons between participants with and without significant amyloid and tau pathology, as well as exploratory analyses into which regions are most significantly affected by Alzheimer’s‐associated synaptic loss.