Aims

To determine whether CSF synaptic biomarkers are associated with Alzheimer’s disease (AD) pathology, and with functional and structural brain alterations in preclinical AD.

Methods

We studied 384 cognitively unimpaired participants of the ALFA+ cohort (249 A-T-, 104 A+T-, 31 A+T+). AT classification was based on CSF Aβ42/40 (A) and CSF p-tau (T). We measured the following CSF synaptic biomarkers: neurogranin (NeuroToolKit, Roche Diagnostics), GAP-43 (ELISA), SNAP-25 and synaptotagmin-1 (IP-MS). Participants underwent [¹⁸F]-flutemetamol and [¹⁸F]-FDG PET, structural MRI, and clinical and neuropsychological evaluations. Centiloid values (CL) and FDG PET and MRI AD-signatures were quantified. Synaptic biomarkers were compared between AT groups (ANCOVA adjusted by age and sex). The association between synaptic biomarkers and continuous variables was studied in linear regression models overall and stratifying by Aβ status.

Results

CSF neurogranin, GAP-43, SNAP-25, and synaptotagmin-1 were increased in the A+T+ group versus A-T-. All biomarkers increased with age, but this increase was specific for A+ participants for CSF neurogranin, GAP-43 and synaptotagmin-1 (Figure 1a).

Higher levels of the four synaptic biomarkers were associated with higher Aβ burden (i.e. lower CSF Aβ 42/40 and higher CL). CSF SNAP-25 and synaptotagmin-1 were already increased in individuals with subthreshold levels of Aβ pathology (20-40 CL).

In A+ participants, higher CSF neurogranin and GAP-43 levels were associated with higher brain metabolism and lower cortical thickness (Figure 1b, c).

Conclusions

Synaptic dysfunction is an early event in AD pathophysiology, and it is associated with metabolic and structural brain alterations in the preclinical stage of Alzheimer’s continuum.