Neurobiological correlates of Mild Behavioral Impairment: a systematic review and meta-analysis

Background: Although individuals with Mild Behavioral Impairment (MBI) show an increased rate of developing dementia, it remains uncertain whether MBI should be considered a risk factor or an actual early sign of neurocognitive disease. Objectives: This systematic review and meta-analysis aimed to explore the association between MBI and neurobiological correlates of dementia. Methods: The study protocol followed PRISMA guidelines and was registered in PROSPERO (CRD42024589059). Five databases and gray literature were systematically searched from inception to January 31, 2025 to identify studies that explored the relationship between MBI and brain imaging findings or neurodegenerative and neuroinflammatory fluid biomarker levels. When studies employed comparable methodologies, a random-effects meta-analysis was performed to summarize the results; conversely, a qualitative synthesis was conducted. The Newcastle-Ottawa Quality Assessment Scale was used to assess the study quality. Results: Of the 834 records, 27 studies were included. Most studies were cross-sectional and examined the presence of structural or functional abnormalities through brain imaging in individuals with MBI. Six studies, 4 of which were longitudinal, focused on MBI and cerebrospinal fluid or plasma biomarkers of neurodegeneration and neuroinflammation. Due to the high methodological heterogeneity across studies, five random-effects meta-analyses were conducted, each including two studies. These analyses reported a positive, cross-sectional correlation between MBI burden and brain deposition of amyloid-beta (Aβ) or tau. Conversely, MBI was not significantly associated with either plasma phosphorylated-tau181 levels or Magnetic Resonance Imaging (MRI) brain atrophy markers. Nevertheless, based on the qualitative synthesis of the 27 included studies, MBI was frequently linked to Alzheimer's disease (AD) abnormalities - both in biomarkers and brain imaging studies. Conclusions: Across studies, MBI appears to be linked to specific neurobiological markers of AD, including Aβ and tau brain deposition, as well as alterations in the mesolimbic pathway and neurodegenerative and neuroinflammatory fluid biomarker levels. Although emerging evidence supports MBI as a potential early clinical sign of AD, heterogeneity across studies precludes definitive conclusions regarding its precise role in the onset and progression of the disease.