Objective: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer’s continuum and associated with Alzheimer’s disease (AD) risk factors, primary pathology, and neurodegeneration markers.

Methods: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker NfL were also measured. Participants underwent structural MRI, and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.

Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE-ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values) and, importantly, the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism, but lower cortical thickness in AD-related brain regions.

Conclusion: CSF synaptic biomarkers increase in early preclinical stages of the Alzheimer’s continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE-ε4, and markers of neurodegeneration.

The ALFA+ study includes 450 cognitively unimpaired participants at increased risk of Alzheimer's disease. The current dataset includes the 397 first consecutive participants with available cerebrospinal fluid biomarkers for Alzheimer's disease pathology and the synaptic biomarkers neurogranin, synaptotagmin-1, SNAP-25 and GAP-43.

CSF β-amyloid (Aβ) status was defined by the CSF Aβ42/40 ratio, and participants were classified as CSF Aβ-positive (A+) if CSF Aβ42/40 < 0.071. Furthermore, the following 3 groups based on both CSF and PET Aβ status (CSF/PET Aβ status groups) were defined: (1) CSF/PET Aβ-negative group (negative CSF Aβ42/40 and Aβ PET <30 Centiloids), (2) group with low burden of Aβ pathology (positive CSF Aβ42/40 but Aβ PET <30 Centiloids), and (3) CSF/PET Aβ-positive (positive CSF Aβ42/40 and Aβ PET ≥ 30 Centiloids).

The following variables are included in the dataset:

Cerebrospinal fluid synaptic biomarkers:

 - "Neurogranin_pgml": referring to Neurogranin (pg/ml)

 - "SYT1_pM": referring to Synaptotagmin-1 (pM)

 - "SNAP-25_pM": referring to synaptosomal-associated protein- 25 (SNAP-25) (pM)

 - "GAP43_pgml": referring to growth-associated protein-43 (GAP-43) (pg/ml)

Participants' classification according to CSF/PET Aβ status groups

- "CSF_PET_Aβ group": referring to CSF/PET Aβ status groups, with 3 levels:

1) "CSF-PET-": CSF/PET Aβ-negative group (negative CSF Aβ42/40 and Aβ PET <30 Centiloids)

2) "CSF+PET-": group with low burden of Aβ pathology (positive CSF Aβ42/40 but Aβ PET <30 Centiloids)

3) "CSF+PET+": positive CSF Aβ42/40 and Aβ PET ≥ 30 Centiloids

Missing values are displayed as "NULL".