Research Summary

Neuropsychiatric Symptoms Associated With Neuroinflammation in Patients With Alzheimer Disease

Anthony Calabro, MA

In a cross-sectional study, researchers found that microglial activation is associated with neuropsychiatric symptoms like irritability, nighttime disturbances, and agitation among patients across the Alzheimer disease continuum. Additionally, the researchers suggest that microglial activation could act as a biomarker for neuropsychiatric symptoms among this patient population.

“Astrocyte and microglial cells are key elements in the brain’s immune milieu, and their aberrant activation may trigger a cascade of inflammatory responses associated with the progression of cognitive decline in individuals with mild cognitive impairment and dementia due to Alzheimer disease,” the authors wrote in their study.

To determine this, researchers developed a cross-sectional study from January to June 2023 using data from the from the Translational Biomarkers in Aging and Dementia cohort at McGill University, in Montreal, Quebec, Canada.

All participants (n = 109) underwent a severity and distress assessment based on the Neuropsychiatry Inventory Questionnaire (NPI-Q), which assesses for 12 neuropsychiatric domains (agitation or aggression, aberrant motor behavior, irritability or lability, elation or euphoria, disinhibition, appetite or eating disturbances, apathy or indifference, delusions, hallucinations, nighttime disturbances, depression or dysphoria, and anxiety).

The participants also underwent magnetic resonance imaging and positron emission tomography for indications of microglial activation, amyloid-β, and tau tangles.

The participants had a study partner (caregiver, family member, or close friend) complete the NPI-Q assessment. The severity score is based on a three-point scale of the patient’s present symptoms within the last month. A score of zero indicates no symptoms. A present symptom was ranked by the partner as either mild (1), moderate (2), or severe (3). The distress score is based on a five-point scale and is associated with the impact of the patient’s symptoms on the caregiver in the past month. A score of zero indicates no distress, while one to five indicates distress and increases with severity.

Of the 109 participants, 72 (66%) were women. The median age of all participants was 71.8 years (age range = 38 to 86.5 years). Among the participants, 70 were cognitively unimpaired, while 39 had cognitive impairment (25 had mild impairment and 14 had Alzheimer disease dementia). Among the 70 who were cognitively unimpaired, 21 were positive for amyloid-β (30%). Of the 39 individuals with cognitive impairment, amyloid-β was found in 31 (79%).

Looking at the NPI-Q severity domains, among all participants, nighttime disturbances were the most prevalent (30 [28%]), followed by irritability (26 [24%]) and appetite or eating disturbances (22 [20%]).

Regarding the NPI-Q distress domains, irritability was the most prevalent (18 [17%]), followed by depression (17 [16%]) and appetite or eating disturbances (14 [13%]).

The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; [95% CI, 1.34 to 13.41]; p = .01). Additionally, the results indicated that irritability (22.8%) was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; [95% CI, 1.77 to 11.95]; p = .008). This was followed by nighttime disturbance (19.3%), agitation (14.1%), and appetite or eating disturbances (12.4%).

Researchers also found that microglia-associated irritability (33.95%) was most associated with study partner burden as measured by NPI-Q distress score (β = 5.72; 95% CI, [0.33 to 11.10]; p = .03).

This study had limitations. For example, the researchers used the NPI-Q assessment, which is a shorter and simpler version of NPI and may not include the frequency of neuropsychiatric symptoms or the subtle changes in the patient’s behavior. Additionally, future studies should include larger population-based cohorts that include all stages of Alzheimer disease.

“In this cross-sectional study of 109 individuals across the Alzheimer disease continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease,” the authors concluded. “Moreover, our findings suggest that the combination of amyloid-β– and microglia-targeted therapies could have an impact on relieving these symptoms.”


Schaffer Aguzzoli C, Ferreira PCL, Povala G, et al. Neuropsychiatric symptoms and microglial activation in patients with Alzheimer disease. JAMA Netw Open. 2023;6(11):e2345175. doi:10.1001/jamanetworkopen.2023.45175