Microglial Activation Contributes to Neuropsychiatric Dysfunction in Alzheimer’s Disease

Background Previous studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the association of MA with neuropsychiatric symptoms (NPS) of individuals across the AD continuum. Method We assessed 132 individuals (86 cognitively unimpaired (CU), 28 MCI, and 18 AD dementia) from the TRIAD cohort who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q), and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same visit. Regions were tailored using Desikan‐Killiany (DK) atlas. SUVRs were calculated using the cerebellum gray matter as a reference. Linear regression tested the association between biomarkers accounting for age, sex, and cognitive status. Result NPI‐Q total score was significantly associated with [11C]PBR28 in the cingulate, inferior temporal, and precuneus accounting for age, sex, and after false discovery rate (FDR) correction for multiple comparisons (Figures 1A, 1B, 1C). This association was independent of Aβ and tau levels (Table 1). Notably, MA predicted neuropsychiatric dysfunction with higher magnitude than Aß or tau using PET values from overlap region (regional SUVR) and if we use a global measure for all tracers (global SUVR) (Figure 2A). When we stratify NPI‐Q domains (agitation, irritability, motor disturbance, disinhibition, elation, delusion, hallucinations, nighttime disturbance, depression, anxiety, apathy, and appetite disturbance) severity score, we found that the hyperactivity subdomain (agitation, irritability, motor disturbance, disinhibition, and elation) showed the larger contribution to the results (Figure 2B). Conclusion Our results suggest MA as a key element associated with neuropsychiatric dysfunction in AD independent of Aβ and tau pathologies. These findings provide additional rationale for the therapeutics targeting glial cells activation in AD patients.