Synaptic proteins relate to memory scores in preclinical Alzheimer’s disease and cognitively healthy controls depending on amyloid

Abstract

Background Memory loss is central to Alzheimer’s disease (AD), but the precise underlying mechanisms remain unclear. Post‐mortem research suggests that synaptic loss best explains symptoms. Here, we investigated in cerebrospinal fluid (CSF) whether levels of synaptic proteins are related with memory scores in older individuals with normal cognition and in preclinical AD. Method Participants were selected from ADNI and EMIF‐AD MBD if they had CSF proteomics and memory scores available. In total, we selected 85 controls (i.e., normal cognition (CN) and normal CSF amyloid‐1‐42 and tau levels; mean±sd age 69±9 years, 58% female) and 46 preclinical AD (i.e. normal cognition and abnormal CSF amyloid‐1‐42 level, normal or abnormal CSF t‐tau and p‐tau; mean±sd age 74±7 years, 50% female). Age‐, sex‐ and education‐specific norms were used to normalize memory tests (ADNI: 30‐minute delayed Rey auditory verbal learning test (ADNI), EMIF: centre‐specific delayed memory tests). We selected 37 proteins available in both cohorts that were specific for synapses according to synGO (https://www.syngoportal.org/), Z‐transformed protein levels relative to controls, and pooled these across cohorts. Protein‐memory associations were assessed with linear models; model1: including covariates education, sex and age; model2: model1 + covariate amyloid status; and model3: model2 + protein level‐amyloid status interaction. Result Memory scores were similar in the preclinical AD and control groups (P=0.52, Figure 1). Three proteins (NCSTN, FGA and NRGN) had increased levels in preclinical AD vs. controls. Across the total group, no proteins were associated with memory functioning. Repeating models including an interaction term with amyloid status showed that 9 synaptic proteins (24.3%) were associated with memory depending on amyloid status. In controls, lower protein levels related with better memory, while in preclinical AD, lower protein levels tended to be related with worse memory (Figure 2). Conclusion Of the synaptic proteins tested, associations with memory were mediated by amyloid status. The finding that lower synaptic protein levels related to better memory in controls, but to worse memory in preclinical AD suggests that synaptic protein levels may reflect different biological processes in these groups.