Finally, TIMS MSI allowed for identifying plaque associated depletion patterns of phosphatidylserine (PS) species that partly overlapped with phosphatidylethanolamine (PE) species, PS 40:7 and PS 40:1 (Figure ). A plaque associated depletion of PS but also PE species has been previously reported for poly-unsaturated fatty acid containing phospholipids, including PE (40:6) and PS (40:6) . In this study we did not observe any PE species that were depleted in Aβ plaque proximity. Therefore, it is possible that previous reports of PE depletion in Aβ plaques proximity might in fact have corresponded to PS species. Nevertheless, in the current study we did not observe PE (40:6) nor PS (36:0). Use of alternative matrix might underlie these differences. Overall, this work highlights the benefits of two dimensions ion separation facilitated through ion mobility. Particularly in the context of MSI lipid research, where convoluted MS spectra are a challenge, the TIMS MSI approach makes it possible to assign m/z values that would otherwise be difficult to attribute to either of the species. and 16:0/18:1, respectively (Suppl.Fig. ). PA is considered a key building block for phospholipid synthesis, and also functions as a second messenger. Although debated, involvement of PA in Alzheimer's disease has been suggested, partially due to the anionic nature of PA and hence it potential role as TREM2 ligand, and partially due to suggested alterations in phospholipases D (PLD) in AD . Specifically, some of the PLD isoforms have been shown to be responsible for PA synthesis from among other cardiolipins (CL) as well as phosphatidylcholine (PC) . Further, while we did not observe a general plaque specific depletion of phosphatidyl-ethanolamine species (PE), likely due to the fact that the previously reported depleted species do rather comprise phosphatidylserines (PS), we do instead observe morphology specific localization of PE. In particular, PE (34:0), were observed to localize to the Aβ plaque cores (Figure ). Alterations in PE levels have been linked to Aβ pathology though modulation of both α-secretase and γ-secretase, with reduction in PE leading to decreased amyloidogenic processing of amyloid precursor protein , likely through influence of biogenesis of mitochondrial outer membrane proteins . Finally, thanks to the TIMS capabilities we were able to observe a unique localization of PS (16:0/22:6) and a second lipid species which we putatively assigned as sulfatide (ST), in particular ST(d36:1) (Figure , Suppl. Fig ). We have previously reported the localization of the ST(d36:1) to the periphery and outside of the Aβ plaques ) however definitive assignment of the ST species was not possible due to the presence of isobaric compounds. Here thanks to the CCS value we were able to attribute the signal depletion at the plaque to the PS species and confidently assign the specific localization towards the plaque rim to ST(36:1) (Suppl.