Human cellular models of the brain to study lipid homeostasis in Alzheimer’s disease and related dementias

Alzheimer’s disease (AD) is a complex neurodegenerative disorder, and the leading cause of dementia worldwide, yet the availability of effective disease-modifying therapeutics remains limited, underscoring the urgent need to identify and comprehensively characterize causative pathogenic mechanisms. While AD is defined by the accumulation of amyloid-β plaques and neurofibrillary tau tangles, converging genetic and molecular evidence positions lipid homeostasis as an underappreciated driver of disease. The identification of APOE4 as the strongest genetic risk factor for late-onset AD, alongside numerous genome-wide association study loci implicating additional genes with established roles in lipid transport, metabolism, and signaling, has catalyzed growing interest in understanding how disrupted cellular lipid biology contributes to neurodegeneration across the brain’s diverse cell types. In this Review, we provide a comprehensive overview of the experimental and computational methodologies available to interrogate lipid biology in human cellular model systems, including mass spectrometry based lipidomics, fluorescent lipid imaging, stable isotope tracing, and multi-omic integration frameworks. We examine findings from differentiated brain-relevant human induced pluripotent stem cell models, detailing the cell-intrinsic lipid vulnerabilities that emerge in the context of AD genetic risk, including disruptions in fatty acid oxidation and lipid droplet dynamics. We further review how multicellular human model systems have begun to illuminate the cell nonautonomous dimensions of lipid dysregulation, particularly the bidirectional intercellular transfer of toxic lipid species between neurons and glia. These cellular findings are contextualized against human postmortem brain and plasma lipidomic studies and complemented by insights from valuable invertebrate and vertebrate model organisms that have identified conserved lipid metabolic pathways governing central nervous system resilience. Finally, we discuss emerging therapeutic strategies targeting lipid biology in AD, with the perspective that a mechanistic understanding of lipid homeostasis across human brain cell types will be essential to the development of the next generation of disease-modifying interventions.