Neuropsychiatric Symptoms and In Vivo Alzheimer's Biomarkers in Mild Cognitive Impairment

Background: Neuropsychiatric symptoms (NPS) carry an increased risk of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). There is a need to understand how to integrate NPS into the paradigm outlined in the 2018 NIA-AA Research Framework. Objective: To evaluate a prediction model of MCI-AD progression using a collection of variables, including NPS, cognitive testing, apolipoprotein E4 status (APOE4), imaging and laboratory AD biomarkers. Methods: Of 300 elderly subjects, 219 had stable MCI and 81 MCI-AD progression over a 5-year follow-up. NPS were measured using the Neuropsychiatric Inventory (NPI). Amultivariate Cox Proportional Hazards Regression Analysis assessed the effects of APOE4, baseline NPI, baseline CSF amyloid-beta, phosphorylated and total tau, baseline AD-signature MRI biomarker, baseline memory and executive function on MCI-AD progression. Results: 27% progressed to dementia (median follow-up = 43 months). NPS were found in stable MCI (62.6%) and MCI-AD converters (70.3%). The Cox model exhibited a good fit (p < 0.001), and NPS (HR = 1.033, p = 0.027), phosphorylated tau (HR = 1.011, p = 0.025), total tau (HR = 1.005, p = 0.024), AD-signature MRI biomarker (HR = 0.111, p = 0.002), executive function (HR = 0.727, p = 0.045), and memory performance (HR = 0.387, p < 0.001) were significantly associated with dementia. Conclusions: NPS may inform dementia risk assessment in conjunction with cognitive testing and imaging and laboratory-AD biomarkers. NPS is independently associated with the risk of MCI-dementia progression, over and beyond the contributions of CSF biomarkers.