Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations

Abstract

Background and objectives: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum.

Methods: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up).

Results: We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted p > 0.05).

Discussion: NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.

Figure 1. Prevalence of Neuropsychiatric Symptoms (NPS) Across a β-Amyloid–Positive (A+) Sample According to Clinical Alzheimer Disease (AD) Stage

*p < 0.05 after correcting for false discovery rate. **p < 0.01 after correcting for false discovery rate. ***p < 0.001 after correcting for false discovery rate. AMB = aberrant motor behaviors; MCI = mild cognitive impairment; SCD = subjective cognitive decline.

Figure 2. Longitudinal Neuropsychiatric Inventory (NPI) Domain Scores and Cognitive Functioning for Individuals With β-Amyloid–Positive Subjective Cognitive Decline at Baseline

Individual trajectories are depicted with model based trends with 95% confidence intervals. Data show the 4 most prevalent neuropsychiatric symptoms at baseline and cognitive domains with most data available. See eFigure 1 (doi.org/10.5061/dryad.hqbzkh1g2) for all data.

Figure 3. Longitudinal Neuropsychiatric Inventory (NPI) Domain Scores and Cognitive Functioning for Patients With β-Amyloid–Positive Mild Cognitive Impairment at Baseline

Individual trajectories are depicted with model based trends with 95% confidence intervals. Data show the 4 most prevalent neuropsychiatric symptoms at baseline and cognitive domains with most data available. See eFigure 2 (doi.org/10.5061/dryad.hqbzkh1g2) for all data.

Figure 4. Longitudinal Neuropsychiatric Inventory (NPI) Domain Scores and Cognitive Functioning for Patients With β-Amyloid–Positive Alzheimer Disease Dementia at Baseline

Individual trajectories are depicted with model based trends with 95% confidence intervals. Data show the 4 most prevalent neuropsychiatric symptoms at baseline and cognitive domains with most data available. See eFigure 3 (doi.org/10.5061/dryad.hqbzkh1g2) for all data.