Neuropsychiatric Symptoms and Alzheimer Disease Biomarkers Independently Predict Progression to Incident Cognitive Impairment

Ganesh M. Babulal, Ling Chen, Samantha A. Murphy, Jason M. Doherty, Ann M. Johnson, John C. Morris

Research output: Contribution to journalArticlepeer-review


Objectives: To investigate the effect of neuropsychiatric symptoms and depression symptoms, respectively, and Alzheimer disease (AD) biomarkers (cerebrospinal fluid [CSF] or Positron Emission Tomography [PET] imaging) on the progression to incident cognitive impairment among cognitively normal older adults. Design: Prospective, observation, longitudinal study. Setting: Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine. Participants: Older adults aged 65 and above who participated in AD longitudinal studies (n = 286). Measurements: CSF and PET biomarkers, Clinical Dementia Rating (CDR), Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Results: Participants had an average follow-up of eight years, and 31 progressed from CDR 0 to CDR >0. After adjusting for sex, age, and education in the Cox proportional hazards survival models, neuropsychiatric symptoms as a time-dependent covariate was statistically significant in the three CSF (Aβ42/Aβ40, t-Tau/Aβ42, p-Tau/Aβ42) PET imaging models (HR = 1.33–1.50). The biomarkers were also significant as main effects (HR = 2.00–4.04). Change in depression symptoms was not significant in any models. The interactions between biomarkers and neuropsychiatric symptoms and depression were not statistically significant. Conclusions: Changes in neuropsychiatric symptoms increase the risk of progression to cognitive impairment among healthy, cognitively normal adults, independent of AD biomarkers. Routine assessment of neuropsychiatric symptoms could provide valuable clinical information about cognitive functioning and preclinical disease state.

Original languageEnglish
Pages (from-to)1190-1199
Number of pages10
JournalAmerican Journal of Geriatric Psychiatry
Issue number12
StatePublished - Dec 2023


  • Biomarkers
  • amyloid imaging
  • cerebrospinal fluid
  • cognitive impairment
  • depression
  • neuropsychiatric symptoms


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