March 18, 2022

Initial Cognitive Manifestation of Dementia Predicts Later Behavioral Symptoms

Risk of agitation, delusions, personality change and more is shaped by early presentation

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The initial predominant indicator of Alzheimer’s or Lewy body dementia — e.g., whether it is memory loss, executive function decline, language deficit or visuospatial dysfunction — is associated with particular later behavioral and psychological changes, finds a new retrospective longitudinal study. Moreover, as dementia progresses, changes such as agitation, apathy, depression, hallucinations and personality change tend to be correlated with the initial cognitive phenotype.


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The study, which analyzed more than 2,400 patients with neuropathologically confirmed Alzheimer’s and/or Lewy body dementia, was published by Cleveland Clinic researchers in JAMA Network Open (2022;5[3]:e220729).

“This is the first study to show that the presenting clinical phenotype — along with neuropathology and a patient’s age and sex — predicts the likelihood of subsequently developing specific behavioral and psychological symptoms,” says the study’s lead author, Jagan Pillai, MD, PhD, staff neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health. “Awareness of these associations can help inform patients and their caregivers of the probable course of their disease and help guide management.”

Dementia-associated symptoms are varied and consequential

The myriad behavioral and psychological symptoms associated with dementia can impact a patient’s functional limitations, caregiver burden, timing of institutionalization and even mortality risk. Different manifestations of dementia are believed to reflect selective regional vulnerability of neuronal populations and patterns of neurofibrillary tangle accumulation and Lewy body pathology, contributing to clinical dementia phenotypes.

Whether a patient’s initial cognitive presentation is associated with the nature and severity of subsequent behavioral and psychological manifestations of dementia had not been previously determined and was the main focus of the current study.

Study design

The study population was taken from the National Alzheimer Coordinating Center database, with records from 37 centers between 2005 and 2019. The analysis included 2,422 patients (59.7% men; mean age, 74.4 years). Patients had neuropathologically confirmed diagnoses of Alzheimer’s disease (n = 1,187), Lewy body dementia (n = 331) or mixed Alzheimer’s disease and Lewy body dementia pathology (n = 904). The mean (± SD) interval from initial visit to autopsy was 5.5 ± 2.8 years.

Initial clinical phenotypes — as determined by the predominant symptom of cognitive decline first recognized by a clinician — were characterized as having primarily amnestic (memory loss), executive (or attention/concentration), language or visuospatial features.


Next, changes in 10 behavioral and psychological symptoms, as determined and noted by the clinician at subsequent patient visits, were identified and compared to the initial phenotype and other patient characteristics and the underlying neuropathology. The 10 symptoms evaluated were agitation, apathy, delusions, depression, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change and rapid eye movement (REM) sleep behavior change.

Neuropsychiatric Inventory Questionnaire data were used to determine severity scores for behavioral and psychological changes.

Findings: various correlations in dementia manifestation

Analysis of the data revealed several patterns in the development of behavioral and psychological symptoms of dementia.

A majority of patients in the cohort had the amnestic phenotype (77%). Compared with these patients with initial amnestic symptoms:

  • Patients with initial language symptoms had lower risk of developing depression, visual hallucinations and REM sleep symptoms but a higher risk of personality changes.
  • Patients with initial executive symptoms had higher risk of developing apathy, delusions, disinhibition, visual hallucinations, personality changes and REM sleep changes.
  • Patients with initial visuospatial symptoms had a higher risk of developing visual hallucinations and REM sleep behavior changes.

In addition, differences were found to be associated with Lewy body disease versus Alzheimer’s disease. Lewy body disease involved:

  • A lower risk for agitation, disinhibition and irritability
  • A higher risk for apathy, depression, REM sleep behavior changes and auditory and visual hallucinations

The following differences were seen in the mixed Alzheimer’s-Lewy body disease group:

  • Higher risk for delusions, REM sleep changes and auditory and visual hallucinations than those in the pure Alzheimer’s disease group
  • Lower risk for visual hallucinations and REM sleep changes than the pure Lewy body disease group

The study also identified younger age as a risk factor for developing most behavioral and psychological symptoms, as well as for greater symptom severity. In addition, low educational level and male sex were associated with more severe symptoms among patients with Alzheimer’s disease or mixed Alzheimer’s-Lewy body dementia.

Overall, women were less likely than men to develop agitation, apathy, visual hallucinations, irritability and REM sleep behavior change, but women had a higher risk of depression.

Symptom changes reflect initial presentation and underlying neuropathology

Dr. Pillai emphasizes two key conclusions from the study. “First, initial cognitive presentation is significantly associated with the development of specific behavioral and psychological symptoms of dementia,” he says. He notes that the mechanism for this observation may be explained by regional differences in brain functions. For example, the prefrontal cortex — associated with executive function — is also thought to play a role in reality-based beliefs, which likely explains the elevated risk of delusions and hallucinations in patients who present initially with executive dysfunction.

“Additionally, the spectrum of behavioral and psychological symptoms reflect the underlying neuropathology,” he says, noting that significant differences were found between patients with Alzheimer’s pathology as opposed to Lewy body pathology.

“These findings collectively provide an important window into the heterogeneity of cortical changes in dementia,” Dr. Pillai concludes. “This is useful to clinicians as they plan patient care and counsel caregivers and family of patients with dementia.”

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