Predicting CSF neurogranin and neurofilament light chain protein levels with a neuropathology‐based APOE genetic risk score

Abstract

AbstractBackgroundCerebrospinal fluid (CSF) levels of neurogranin, an index of synaptic degeneration, and neurofilament light chain (NfL), an index of neuroaxonal degradation, are both biomarkers of neurodegeneration in Alzheimer’s disease (AD). The presence of APOE is the strongest genetic risk factor for late onset AD and has also been associated with increased CSF neurogranin, a marker of neurodegeneration. To test the association between APOE and CSF biomarkers for neurodegeneration, we used a neuropathology‐based weighted risk score for APOE genotype (APOE‐npscore) and hypothesized that greater AD risk as indexed by the APOE‐npscore would be associated with higher CSF concentrations of neurogranin and NfL.MethodWe examined data collected from participants in the Wisconsin Registry for Alzheimer’s Prevention (n = 243) (avg age = 65) and Wisconsin Alzheimer’s Disease Research Center (n = 411) (avg age = 64) including participants with Dementia (n = 50) Impaired‐Other (n = 8), Mild Cognitive Impairment (MCI) (n = 55), and cognitively unimpaired (n = 545) participants. The CSF biomarkers were measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Using linear regression, we tested associations between the APOE‐npscore and CSF neurogranin and NfL concentrations, adjusting for age at lumbar puncture (LP) and sex. We also tested for interactions between age at LP or sex and the APOE‐npscore.ResultsThe APOE‐npscore was significantly associated with CSF neurogranin concentration (β = 3.126, p < 0.01) but not significantly associated with CSF NfL concentration (β = 39.570, p > 0.05). Age at LP was significantly associated (p < 0.001) with CSF neurogranin and NfL concentrations. No significant interactions were found between the APOE‐np score and age at LP or sex in either test. APOE‐npscore, age at LP, and sex accounted for 7% of the variability of CSF neurogranin, and 27% of CSF NfL.ConclusionsThe current study lends additional support to the impact of APOE on neurodegeneration, and supports the utility of using the APOE‐npscore to index risk of AD. The effects of APOE were observed on markers of synaptic degeneration, which underscores the importance of synaptic dysfunction in AD.