Modifying effect of AD pathology in the association between CSF synaptic biomarkers and brain function and structure in preclinical Alzheimer

Abstract Background Previous studies have shown that synaptic biomarkers are increased in CSF in the preclinical stage of Alzheimer’s disease (AD). However, little is known about how CSF synaptic biomarkers associate with structural and functional brain measures in preclinical Alzheimer. The aim of this study was to test the association of CSF synaptic biomarkers with brain metabolism and structure in preclinical Alzheimer and explore whether these associations were modified by AD pathology. Method We studied 328 cognitively‐unimpaired individuals of the ALFA+ cohort. Participants underwent lumbar puncture, [18F]‐FDG PET scan and structural MRI. The following synaptic biomarkers were measured in CSF: neurogranin (NeuroToolKit [a panel of automated robust prototype immunoassays], Roche Diagnostics International Ltd), GAP‐43 (ELISA), SNAP‐25 and synaptotagmin‐1 (IP‐MS). We performed voxel‐wise analyses to test the association of each synaptic biomarker with brain metabolism and grey matter volume, using a threshold of p<0.005 and a minimum cluster size of 100 voxels. Participants were categorized by AT groups (A+ if CSF Aβ42/40<0.071 and T+ if CSF p‐tau>24pg/ml) and interaction terms with each synaptic biomarker were evaluated. Result 212 (64.6%) participants were A‐T‐, 91 (27.7%) were A+T‐ and 25 (7.6%) were A+T+. To focus the study on the AD continuum , A‐T+ participants (n=12) were excluded. When assessing all participants, positive associations between each CSF synaptic biomarkers and FDG PET uptake and grey matter volume were found in brain areas including the caudate, the insula, cingulate gyrus and inferior temporal and parietal gyrus (Fig 1A). AT status modified the associations with both FDG PET uptake and grey matter volume. Compared to A‐T‐, A+T+ participants showed a positive association of CSF neurogranin, GAP‐43 and synaptotagmin‐1 with FDG PET uptake in the precuneus. Conversely, CSF synaptic biomarkers were negatively associated with grey matter volume with progressive AD pathology (A‐T‐>A+T‐>A+T+) in several brain regions including the cingulate gyrus and middle and superior frontal gyrus (Fig 1B). Conclusion In preclinical Alzheimer, CSF synaptic biomarkers show associations with functional and structural brain measures, which are modified by AD pathology. Progressive AD pathology is associated with increased brain metabolism and decreased grey matter volume in several AD‐related brain regions.