Changes to Behavioral and Psychological Symptoms of Dementia Differ by Gender, Age, Neuropathology, Baseline Phenotype

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Investigators from the Cleveland Clinic sourced data from the National Alzheimer Coordinating Center database to evaluate clinical phenotypes associated with the severity and nature of behavioral and psychological symptoms of dementia.

Risk for behavioral and psychological symptoms of dementia (BPSDs) were found to differ on the basis of age, gender, baseline cognitive phenotype, and underlying neuropathology, according to results of a retrospective longitudinal cohort study, published in JAMA Network Open.

Investigators from the Cleveland Clinic sourced data from the National Alzheimer Coordinating Center database which was collected at 37 centers between 2005 and 2019. Patients with Alzheimer disease pathology (ADP; n=1187), Lewy body-related pathology (LRP; n=904) or mixed ADP-LRP pathology (n=331) were assessed for long-term changes across 10 BPSDs.

The ADP, LRP, and mixed groups were aged mean 75.2, 74.9, and 73.1 years at baseline (P <.001); 45.7%, 27.2%, and 37.9% were women (P <.001); and 58.4%, 34.6%, and 62.6% were apolipoprotein E positive (P <.001), respectively. Mean time to follow-up ranged between 3.1 and 3.8 years and time to death ranged from 4.7 to 5.8 years.

Among all participants, age at first visit was negatively associated with changes to agitation, apathy, depression, disinhibition, visual hallucinations, irritability, personality change, and rapid eye movement (REM) sleep behavior (all P <.05). Female gender was negatively associated with changes in agitation, apathy, visual hallucinations, irritability, and REM sleep behavior and positively associated with depression (all P <.05).

Stratified by ADP, LRP, and mixed-status, group differences were observed for changes to agitation, anxiety, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, and REM sleep behavior (all P ≤.03).

The mixed group was at higher risk for delusions (hazard ratio [HR], 1.27), auditory hallucinations (HR, 1.62), visual hallucinations (HR, 1.57), and REM sleep behavior (HR, 2.10) changes compared with the ADP cohort. Compared with LRP, the mixed group was at lower risk for visual hallucinations (HR, 0.56) and REM sleep behavior changes (HR, 0.44).

The LRP cohort was associated with increased risk for apathy (HR, 1.19), depression (HR, 1.32), auditory hallucinations (HR, 2.00), visual hallucinations (HR, 2.78) and REM sleep behavior (HR, 4.77) changes and decreased risk for agitation (HR, 0.74), disinhibition (HR, 0.78), and irritability (HR, 0.81) changes compared with ADP.

Stratified by neuropathology, patients with executive symptoms were at increased risk for agitation (HR, 1.28), apathy (HR, 1.62), delusions (HR, 1.77), disinhibition (HR, 1.47), visual hallucinations (HR, 1.63), personality (HR, 2.45), and REM sleep behavior (HR, 1.71) changes. Patients with language symptoms were at increased risk for personality changes (HR, 1.42) and at a decreased risk for depression (HR, 0.79), visual hallucinations (HR, 0.57), and REM sleep behavior (HR, 0.43) changes. The patients with visuospatial symptoms were associated with changes in visual hallucinations (HR, 2.51) and REM sleep behavior (HR, 1.91).

This study may not be generalizable to nonwestern populations as all data were sourced in the United States.

“The findings of this cohort study suggest that differences in neuropathology and the nature of the clinical phenotype, in addition to age, sex, and educational level, are important when exploring the impact of specific neural substrates of BPSDs in neurodegenerative diseases and evaluating clinical outcomes. Awareness of these associations could be helpful in dementia management,” concluded the study authors.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Pillai JA, Bena J, Rothenberg K, Boron B, Leverenz JB. Association of variation in behavioral symptoms with initial cognitive phenotype in adults with dementia confirmed by neuropathology. JAMA Netw Open. 2022;5(3):e220729. doi:10.1001/jamanetworkopen.2022.0729