Research models to study lewy body dementia

Abstract

Abstract Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer’s disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and amyloid plaques. These pathological features position LBD as a comorbid condition of both Parkinson’s disease (PD) and AD, with over 50% of LBD cases exhibiting co-pathologies. LBD’s mixed pathology complicates the development of comprehensive models that reflect the full spectrum of LBD’s etiological, clinical, and pathological features. While existing animal and cellular models have facilitated significant discoveries in PD and AD research, they lack specificity in capturing LBD’s unique pathogenic mechanisms, limiting the exploration of therapeutic avenues for LBD specifically. This review assesses widely used PD and AD models in terms of their relevance to LBD, particularly focusing on their ability to replicate human disease pathology and assess treatment efficacy. Furthermore, we discuss potential modifications to these models to advance the understanding of LBD mechanisms and propose innovative research directions aimed at developing models with enhanced etiological, face, predictive, and construct validity.