Cell-Type-and Isoform-Specific Roles of Fatty Acid-Binding Proteins in Alzheimer’s Disease: An Evidence-to-Action Framework

Brain lipid dysregulation accompanies Alzheimer’s disease (AD), but the contribution of individual lipid-handling proteins to disease progression remains uncertain. Fatty acid-binding proteins (FABPs) link intracellular fatty-acid trafficking to signaling and differ in their cellular distribution and ligand interactions. This critical narrative review examines FABP3, FABP5 and FABP7, drawing distinctions among human associations, perturbation studies in AD-relevant models, and mechanisms inferred from other experimental settings. Cerebrospinal fluid FABP3 is associated with amyloid burden, regional atrophy and cognitive decline, although its disease specificity and added diagnostic value remain uncertain. Endothelial FABP5 supports docosahexaenoic acid handling in experimental systems, but evidence that selectively increasing its activity modifies AD is lacking. FABP7 abundance increases in plaque-associated astrocytes, and overexpression experiments implicate ligand binding in inflammatory signaling. Whether endogenous FABP7 drives astrocyte dysfunction in human AD remains unknown. Conversely, neuronal fabp perturbation in Drosophila supports a protective role in amyloid-related phenotypes, but leaves the functions of individual mammalian isoforms unresolved. A proposed arachidonic-acid/docosahexaenoic-acid switch and apoE-dependent regulation of FABP7 suggest mechanisms to test, but do not yet provide a basis for treatment. The evidence-to-action framework identifies distinct priorities: incremental biomarker validation for FABP3, selective neurovascular perturbation for FABP5, and cell- and ligand-resolved experiments for FABP7. Clinical translation will require distinguishing changes that accompany tissue injury from mechanisms that can be modified to improve disease-relevant outcomes.