Neuropsychiatric symptoms in cognitively normal older persons, and the association with Alzheimer’s and non-Alzheimer’s dementia

Abstract

Background: Neuropsychiatric symptoms (NPS) have been reported to be useful in predicting incident dementia among cognitively normal older persons. However, the literature has not been conclusive on the differential utilities of the various NPS in predicting the subtypes of dementia. This study compared the risks of Alzheimer's and non-Alzheimer's dementia associated with the various NPS, among cognitively normal older persons. Methods: This cohort study included 12,452 participants from the Alzheimer's Disease Centers across USA, who were ≥ 60 years and had normal cognition at baseline. Participants completed the Neuropsychiatric Inventory-Questionnaire at baseline and were followed up almost annually for incident dementia (median follow-up = 4.7 years). Symptom clusters of NPS-as identified from exploratory and confirmatory factor-analyses-were included in the Cox regression to investigate their associations with incident dementia. Results: The various NPS showed independent yet differential associations with incident dementia. Although psychotic symptoms were rarely endorsed by the participants, they predicted much higher risk of dementia (HR 3.6, 95% CI 2.0-6.4) than affective symptoms (HR 1.5, 95% CI 1.2-1.8) or agitation symptoms (HR 1.6, 95% CI 1.3-2.1). Psychotic symptoms predicted all dementia subtypes, while affective and agitation symptoms differentially predicted some subtypes. Across dementia subtypes, psychotic symptoms had relatively higher risk estimates than affective or agitation symptoms, with the risk estimates being particularly high in non-Alzheimer's dementia. Conclusions: Among cognitively normal individuals, the presence of NPS may warrant greater clinical vigilance as precursors to dementia and its subtypes. The findings highlight the need for further research to enrich our understanding on the neurobiological links between various NPS and dementia subtypes. They may also change the clinical approach in managing late-life psychotic symptoms, requiring a greater emphasis on dementia surveillance in the diagnostic criteria of late-life psychotic disorders.

Trajectories of subjective cognitive decline, and the risk of mild cognitive impairment and dementia

“…The Cox regression adjusted for demographic information (age, sex, and ethnicity), known predictors of neurocognitive disorders (years of education, APOE e4 status, current smoking, diabetes mellitus, hypertension, hyperlipidemia, and MMSE score) [ 29 ], as well as potential confounders [ 30 ] that may predict both the exposure-of-interest (SCD) and the outcome-of-interest (neurocognitive disorders), namely GDS score and presence of anxiety symptoms. GDS score was included as a potential confounder because depressive symptoms are strongly associated with SCD (exposure-of-interest) [ 1 , 8 , 31 , 32 ], while at the same time, the presence of depressive symptoms has been shown to be an independent predictor of neurocognitive disorders (outcome-of-interest) [ 3 , 33 – 35 ]. Similarly, anxiety symptoms are known to correlate with SCD (exposure-of-interest) [ 2 ], and the presence of anxiety symptoms has also been reported to predict neurocognitive disorders (outcome-of-interest) [ 33 – 39 ].…”

“…GDS score was included as a potential confounder because depressive symptoms are strongly associated with SCD (exposure-of-interest) [ 1 , 8 , 31 , 32 ], while at the same time, the presence of depressive symptoms has been shown to be an independent predictor of neurocognitive disorders (outcome-of-interest) [ 3 , 33 – 35 ]. Similarly, anxiety symptoms are known to correlate with SCD (exposure-of-interest) [ 2 ], and the presence of anxiety symptoms has also been reported to predict neurocognitive disorders (outcome-of-interest) [ 33 – 39 ].…”

“…The probabilities of being “complete cases” (those with follow-up data) were generated from logistic regression. The inverse of the probabilities was then used as weights in Cox regression, so that the results bear more semblance to those who dropped out and are less biased towards participants who provided follow-up data [ 3 , 33 , 34 , 41 ]. Further details on IPW are available in Additional file 1 .…”

Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers—results from the DELCODE study

“…However, results from a Mexican cohort study showed that certain NPS were independent predictors of incident dementia after 3 years [15] and data from the Mayo Clinic Study of Aging indicated that agitation, apathy, anxiety, irritability, and depression in cognitively normal persons predicted incident MCI [10]. Results from a recent longitudinal study on cognitively normal persons showed that psychotic, affective, and agitation symptoms predicted Alzheimer's dementia, among other dementia subtypes [5].…”

“…Among the most common NPS in patients with mild cognitive impairment (MCI) and early AD are depression, agitation, and apathy [2], but also anxiety and irritability that show a high prevalence especially in MCI [3,4]. In cognitively normal persons of the National Alzheimer's Coordinating Center (NACC) database who progressed to dementia over the median follow-up of 4.7 years, the most prevalent NPS were depression, irritability, sleep disturbances, appetite changes, and anxiety [5].…”