Synaptic markers are associated with cognitive decline after accounting for amyloid burden among an at-risk Alzheimer's disease cohort.

Amyloid burden impacts cognitive decline in the pre-dementia stages of Alzheimer's disease (AD), but there remains significant variability in cognitive trajectories that may be explainable by markers of synaptic function and neurodegeneration. Leveraging longitudinal data from two harmonized, at-risk but predominantly unimpaired cohorts, we examined how several proteins measured from cerebrospinal fluid (CSF) differ by amyloid status, cognitive status, and impact cognitive decline measured using a Preclinical Alzheimer's Cognitive Composite. Four hundred and thirty-four individuals provided CSF biomarkers of amyloid-beta42 (ab42), phosphorylated tau (181), from which we identified Aβ + individuals using a cutoff based on a p-tau181/Aβ42 ratio. Other markers of neurodegeneration (N) included neurofilament light, neurogranin, SNAP-25, and NPTX2. Most biomarkers of N were higher in the Aβ + group and lower in cognitively unimpaired individuals, though NPTX2 exhibited the opposite pattern. Even in the face of Aβ+, NPTX2 was higher in individuals who showed slower rates of cognitive decline, suggesting NPTX2 may be associated with cognitive resilience. Moreover, a SNAP-25/NPTX2 ratio of synaptic dysfunction explained more variance in cognitive decline than other biomarkers alone. This work provides support for potentially useful biomarkers of synaptic function implicated in the clinical syndrome of AD, aiding in future diagnosis and staging efforts.