Synaptic proteins in pre‐symptomatic Alzheimer's disease: genes implicate synaptic biomarkers to the early detection of cognitive decline

Abstract Background The heterogeneous etiology of “sporadic” Alzheimer’s disease (sAD) includes genetic influences. To better understand synaptic dysfunction in AD pathogenesis, we used protein quantitative train loci (pQTL) assessments and a polygenic risk score (PRS) to examine the relationship between synaptic integrity and longitudinal cognitive performance in the presymptomatic phase of the disease. Method The PREVENT‐AD cohort includes symptom‐free elderly participants at risk of AD because of their family history. A second resource, the Quebec Founder Population (QFP) brain bank, derives from the descendants of the 17 th and 18 th century French settlers in Eastern Canada. We used Olink Proximity Extension Assays to measure the soluble synaptic proteins ADAM 22 (post‐synaptic) and ADAM23 (pre‐synaptic) in 120 CSFs, while immunoprecipitated SYT1 (pre‐synaptic) and SNAP25 (pos‐synaptic) were analyzed in 141 CSF samples using a quadrupole–orbitrap mass spectrometer. The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) indicated cognitive trajectory. Genotyping was performed using the Illumina Infinium Omni 2.5M‐8 array. Cortical RNAs (n=86) from the QFP cohort were processed using GeneChip WT Pico Kit. Statistical analyses included sex, education and APOE e4 status as covariates. Result Among PREVENT‐AD participants who remained cognitively unimpaired over the past 11 years, we observed significant correlations between a PRS constructed from pQTL ADAM 22 CSF concentrations and delayed memory (R 2 = 0.06, p = 0.0132), visuospatial constructional memory (R 2 = 0.274, p = 0.00408) and total index scale (R 2 = 0.202, p = 0.0454), but only trend‐levels association with immediate memory (R 2 = 0.1, p = 0.0747). We also found similar correlations between PRS constructed from of CSF ADAM 23, CSF SYT1, CSF SNAP25 concentrations and the different RBANS subscales. Significantly lower cortical mRNA levels for ADAM22 (p = 0.062), ADAM23 (p = 0.0030), SYT1 (p = 0.033) and SNAP25 (p = 0.0036) were found in the autopsied AD brains compared to autopsied control brains. Conclusion CSF synaptic protein levels show promising correlations with emerging cognitive deficits and provide insights toward a possible compensatory mechanism in the early presymptomatic phase of the disease.