O4-04-03: the biological basis of cognitive impairment due to suspected non-alzheimer's pathology (snap): study design and baseline cohort features

Accumulation of amyloid-beta and hyper-phosphorilated tau, as well as neurodegeneration, are the core pathological processes of Alzheimer's disease (AD) but their interplay is still unclear. Clarifying the different pathways leading to neurodegeneration is an urgency, since approximately 25% of individuals present neurodegeneration without amyloidosis, a condition called suspected non-Alzheimer's pathology (SNAP). The “SNAP” project aims to investigate pathways to neurodegeneration onset, progression, and distribution in amyloid-dependent and independent cognitive deterioration. Here, we present the study design and baseline cohort features, stratified by amyloid status (A+,A-). The “SNAP” project will include 220 cognitively impaired (CI) and 80 cognitively normal (CN) participants enrolled at the Geneva Memory Clinic since 2016. They undergo multi-modal imaging and clinical protocols including: (i)clinical and neuropsychological assessments; (ii)3T-MRI; (iii)FDG-PET; (iv)Amyloid-PET; and in a subsample: (v)Tau-PET; (vi)EEG; (vii)7T-MRI; (viii)CSF studies; (ix)gut and saliva microbiotas studies. Up to now, 127 CI and 30 CN completed clinical, neuropsychological and imaging assessments. Sample features were analysed using the Mann-Whitney test for continuous variables and Chi-squared test for categorical ones. CI are older than CN (mean±SD: 74±7 vs. 70±7, p<0.001) and less educated (mean±SD years: 12±4 vs. 16±3, p<0.001). CI are more frequently amyloid-positive and tau-positive (71% vs. 27%, p<0.001; 53% vs. 0%, p<0.002, respectively), have a higher amyloid burden (standardized uptake value ratio: 1.26±0.36 vs. 1.05±0.25, p=0.001) and more severe medial temporal lobe atrophy (MTA-scale median[interquartile range, IQR]: 1[1] vs. 0[1], p<0.001). No differences in vascular damage are observed (ARWMC scale median[IQR]: 7[6] vs. 6[5], p=0.394). Comparisons within sub-samples show no significant differences between CN/A+ and CN/A- sub-groups; CI/A+ and CI/A- are matched for age, gender, education and MMSE but differ in frequency of tau-positivity (73% vs. 12%, p<0.001) and Braak-stages (median[IQR]: 4[4] vs. 0[0], p<0.001), MTA (median[IQR]: 2[1] vs. 1[1], p=0.015), left and right hippocampal volumes (mm2, 3296.6±504.7 vs. 3483.5±581.4; 3375.6±528.7 vs. 3591.6±552.1, p<0.05) and left entorhinal thickness (2.9±0.5 vs. 3.1±0.4, p=0.018). In these preliminary results, CI/A+ represents a population with AD features including high amyloid burden, MTA and a high frequency of tau-positivity. Further analyses will allow a greater insight in the biological pathways linking amyloid and tau pathology to neurodegeneration and cognitive impairment.