CSF synaptic biomarkers in the preclinical stage of Alzheimer’s disease and their association with MRI and PET markers of neurodegeneration: a cross-sectional study

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.