CSF SNAP‐25 and Neuronal pentraxin 2 associations with cognitive decline in the presence of CSF ptau181/Aβ42 in an at‐risk cohort

Abstract Background Alzheimer's disease (AD) is identified by the accumulation of amyloid β (Aβ) and tau proteins in the brain. The NeuroToolKit offers automated cerebrospinal fluid (CSF) immunoassays of core AD biomarkers and biomarkers of neurodegeneration and synaptic function, including neurofilament light (NfL), SNAP‐25, and neuronal pentraxin 2 (NPTX2). This work explores whether these three markers predict pre‐dementia cognitive decline synergistically with or after accounting for CSF ptau 181 /Aβ 42 . Method Participants included N=360 baseline dementia‐free adults (45—85 years) with complete CSF biomarker and cognitive data from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (on‐going, longitudinal preclinical AD studies). We assessed CSF biomarkers using the NeuroToolKit (NTK), a panel of robust prototype biomarker assays (Roche Diagnostics International, Switzerland). Mixed models examined separately whether NfL, SNAP‐25, or NPTX2 biomarkers further modified Preclinical Alzheimer’s Cognitive Composite (PACC3) trajectories beyond Aβ+ effects. Biomarker*ptau 181 /Aβ 42 *age (linear and quadratic) interactions were examined, and non‐significant higher order interactions removed sequentially before interpreting NfL, SNAP‐25, and NPTX2 effects. Result Sample characteristics are shown in Table 1, and show significant correlations among all biomarker pair except NPTX2 and ptau 181 /Aβ 42 . Table 2 and Figure 1 depict PACC3 model outputs and biomarker associations; Aβ+ performed worse or declined faster than Aβ‐ across all models. Compared to a base “amyloid‐only” model, NfL, SNAP‐25, and NPTX2 “biomarker” models showed an improved model fit (Table 2). The best‐fitting model included the NPTX2* ptau 181 /Aβ 42 *age 2 interaction (Table 2) which showed greatest average PACC3 decline in those with higher amyloid and lower NPTX2 (Figure 1d). SNAP‐25 also related to cognition such that individuals with lower amyloid and higher SNAP‐25 had the highest PACC3 average (interactions with age were non‐significant), and individuals with higher NfL showed steeper PACC3 decline than those with lower NfL. Conclusion In addition to known effects of NfL, recently developed NTK immunoassays for SNAP‐25 and NPTX2 accounted for additional variability on AD‐related pre‐dementia PACC3 performance. Future work may identify clinically useful cutpoints for SNAP‐25 and NPTX2 and explore relations with other biomarkers common to neurodegeneration and AD. We will also examine associations with other outcomes including clinical progression of AD.