Polymorphic Aβ pathology involves structurally different amyloid aggregates within and across different plaque phenotypes . Most prominently, neuritic plaques associated with AD pathology, are characterized by formation of a compact core that was found to consist mainly of Aβ 1-40 . With background to the complexity of plaque pathology and still limited knowledge thereof, it comes to no surprise that major pharmacotherapeutic strategies targeting Aβ plaque pathology have not been successful so far. This, in turn, highlights the immediate need to further elucidate the molecular architecture associated with plaque formation in AD. Indeed, key developments in bioanalytical techniques, including chemical imaging, have increased our understanding of the molecular basis of single Aβ deposit formation at subcellular scales. Particularly, mass spectrometry imaging (MSI) has gained prominent relevance for studying biochemical traits of AD pathology warranted by the molecular specificity inherent to this technique . Here, matrix assisted laser desorption ionization (MALDI) based MSI has been demonstrated to be a valuable approach in retrieving novel chemical information on plaque pathology in both AD patient's brain and AD mouse models. This includes also molecular information on plaque associated neuronal lipid dynamics, which is significant in that lipids have been implicated in AD pathology and more specific in Aβ plaque formation mechanisms before . This is corroborated by the fact that the ε4 allele of the apolipoprotein E gene (APOE), a lipid transporter, is the most prominent genetic risk factor for developing AD . While the relevance of lipids in AD pathology has long been recognized, the means for elucidating lipid biochemistry comprehensively and chemically specific at single plaque scales have not been available. Here, MALDI MSI along with complementary chemical amyloid staining to delineate and annotate plaque polymorphism, identified plaque morphology associated sphingolipid-(SP), phosphatidylcholine-(PC), lysolipid-(LPC/LPA) and phosphoinositol (PI), species .