Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data

J Alzheimers Dis. 2017;55(4):1519-1528. doi: 10.3233/JAD-160780.


Background: Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD.

Objective: To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD.

Methods: Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons.

Results: 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits.

Conclusions: Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Keywords: (p)-TDP-43; Alzheimer’s disease; aggression; agitation; neuropathology; traumatic brain injury; vascular lesions; vascular risk factors.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aggression / physiology*
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / physiopathology*
  • Autopsy
  • DNA-Binding Proteins / metabolism
  • Depression / epidemiology
  • Depression / pathology
  • Female
  • Hallucinations / epidemiology
  • Hallucinations / pathology
  • Humans
  • Lewy Body Disease / epidemiology
  • Lewy Body Disease / pathology
  • Male
  • Mental Status Schedule
  • Psychomotor Agitation / epidemiology
  • Psychomotor Agitation / etiology*
  • Retrospective Studies
  • Risk Factors
  • Statistics, Nonparametric


  • DNA-Binding Proteins
  • TARDBP protein, human