• Miriam Rabl, Christopher Clark, Loïc Dayon, Julius Popp, and Alzheimer’s Disease Neuroimaging Initiative.
• Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Psychiatric University Hospital, Zurich, Switzerland.
• J. Neurol. Neurosurg. Psychiatr. 2024 Sep 17.

Background And ObjectivesNeuropsychiatric symptoms (NPS) are common in older people with cognitive impairment and Alzheimer's disease (AD). No biomarkers to detect the related pathology or predict the clinical evolution of NPS are available yet. This study aimed to identify plasma proteins that may serve as biomarkers for NPS and NPS-related clinical disease progression.MethodsA panel of 190 plasma proteins was quantified using Luminex xMAP in the Alzheimer's Disease Neuroimaging Initiative cohort. NPS and cognitive performance were assessed at baseline and after 1 and 2 years. Logistic regression, receiver operating characteristic analysis and cross-validation were used to address the relations of interest.ResultsA total of 507 participants with mild cognitive impairment (n=396) or mild AD dementia (n=111) were considered. Selected plasma proteins improved the prediction of NPS (area under the curve (AUC) from 0.61 to 0.76, p<0.001) and future NPS (AUC from 0.63 to 0.80, p<0.001) when added to a reference model. Distinct protein panels were identified for single symptoms. Among the selected proteins, ANGT, CCL1 and IL3 were associated with NPS at all three time points while CCL1, serum glutamic oxaloacetic transaminase and complement factor H were also associated with cognitive decline. The associations were independent of the presence of cerebral AD pathology as assessed using cerebrospinal fluid biomarkers.ConclusionsPlasma proteins are associated with NPS and improve prediction of future NPS.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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