# Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease **Authors:** Daan van der Vliet, Luuk E. de Vries, Xinyu Di, Dennis Wever, Brechtje de Jong, Marc T. C. van der Meij, Marielle van der Peet, Amy C. Harms, Thomas Hankemeier, Dick F. Swaab, Inge Huitinga, Joost Verhaagen, Mario van der Stelt PMC · DOI: 10.1002/alz.71083 · Alzheimer's & Dementia · 2026-02-03 ## TL;DR This study finds that reduced triacylglycerols and lipid droplets are linked to resilience against Alzheimer's disease despite brain pathology. ## Contribution The study identifies lipidomic differences between Alzheimer's patients and resilient individuals using multi-omics analysis. ## Key findings - ω6-derived oxylipins are elevated in both Alzheimer's and resilient donors. - Resilient individuals have lower triacylglycerols and lipid droplets compared to Alzheimer's patients. - Increased oxylipins and loss of inhibitory neurons correlate with amyloid beta plaque load. ## Abstract Although it has become clear that alterations in lipid metabolism are associated with Alzheimer's disease (AD), it is unclear how they contribute to both cognitive decline and the pathophysiology of AD. Lipidomics and activity‐based protein profiling (ABPP) were performed in the frontal cortex of control, AD and resilient donors, that is, individuals with AD pathology without cognitive decline. The most pronounced alterations in lipids were in ω6‐derived oxylipins, which were particularly increased in AD. Triacylglycerols (TAGs) and lipid droplets (LDs) were more abundant in the AD donors compared to the resilient donors. Multi‐omics factor analysis (MOFA) showed that increased ω6‐derived oxylipins and the loss of inhibitory neurons were associated with amyloid beta (Aβ) plaque load. Our multi‐omics data show a molecular response associated with Aβ load shared among AD and resilient donors, but reduced LDs in resilient donors compared to AD. Comprehensive lipidomics analysis of frontal cortex from controls, Alzheimer's disease (AD) patients and resilient individuals.ω6 Oxylipins, markers of neuroinflammation, are increased in both AD and resilience.Resilient donors have reduced triacylglycerols and lipid droplets compared to AD.Multi‐omics integration shows a molecular response to amyloid beta plaques associated with ω6‐derived oxylipins and loss of interneurons. Comprehensive lipidomics analysis of frontal cortex from controls, Alzheimer's disease (AD) patients and resilient individuals. ω6 Oxylipins, markers of neuroinflammation, are increased in both AD and resilience. Resilient donors have reduced triacylglycerols and lipid droplets compared to AD. Multi‐omics integration shows a molecular response to amyloid beta plaques associated with ω6‐derived oxylipins and loss of interneurons. ## Linked entities - **Chemicals:** triacylglycerols (PubChem CID 5460048) - **Diseases:** Alzheimer's disease (MONDO:0004975) ## Full-text entities - **Genes:** MGLL (monoglyceride lipase) [NCBI Gene 11343] {aka HU-K5, HUK5, MAGL, MGL}, AIF1 (allograft inflammatory factor 1) [NCBI Gene 199] {aka AIF-1, IBA1, IRT-1, IRT1}, PPME1 (protein phosphatase methylesterase 1) [NCBI Gene 51400] {aka ABDH19, PME-1}, UCHL1 (ubiquitin C-terminal hydrolase L1) [NCBI Gene 7345] {aka HEL-117, HEL-S-53, NDGOA, PARK5, PGP 9.5, PGP9.5}, VGF (VGF nerve growth factor inducible) [NCBI Gene 7425] {aka SCG7, SgVII}, Iba1 (induction of brown adipocytes 1) [NCBI Gene 114737], ABAT (4-aminobutyrate aminotransferase) [NCBI Gene 18] {aka GABA-AT, GABAT, NPD009}, Gm12551 (perilipin 2 pseudogene) [NCBI Gene 101055843], APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, Aif1 (allograft inflammatory factor 1) [NCBI Gene 11629] {aka AIF-1, D17H6S50E, G1, Iba1}, Gfap (glial fibrillary acidic protein) [NCBI Gene 14580], APOE (apolipoprotein E) [NCBI Gene 348] {aka AD2, APO-E, ApoE4, LDLCQ5, LPG}, PLIN2 (perilipin 2) [NCBI Gene 123] {aka ADFP, ADRP}, PAFAH1B3 (platelet activating factor acetylhydrolase 1b catalytic subunit 3) [NCBI Gene 5050] {aka PAFAHG}, TPP2 (tripeptidyl peptidase 2) [NCBI Gene 7174] {aka IMD78, TPP-2, TPP-II, TPPII}, TARDBP (TAR DNA binding protein) [NCBI Gene 23435] {aka ALS10, TDP-43}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, LIPE (lipase E, hormone sensitive type) [NCBI Gene 3991] {aka AOMS4, FPLD6, HSL, LHS, REH}, CCK (cholecystokinin) [NCBI Gene 885], PAFAH1B2 (platelet activating factor acetylhydrolase 1b catalytic subunit 2) [NCBI Gene 5049] {aka HEL-S-303}, SST (somatostatin) [NCBI Gene 6750] {aka SMST, SST1}, ABHD6 (abhydrolase domain containing 6, acylglycerol lipase) [NCBI Gene 57406] - **Diseases:** mitochondrial dysfunction (MESH:D028361), neuroinflammation (MESH:D000090862), neurological or psychiatric diseases (MESH:D001523), Lewy bodies (MESH:D020961), Dementia (MESH:D003704), neuropathology (MESH:D009422), hemorrhages (MESH:D006470), amyloid (MESH:C000718787), hippocampal sclerosis (MESH:D000092223), AD (MESH:D000544), PMD (MESH:D000094025), RESEARCH (MESH:D014947), cognitive decline (MESH:D003072), edema (MESH:D004487), gliosis (MESH:D005911), Inflammatory (MESH:D007249) - **Chemicals:** formalin (MESH:D005557), nitrogen (MESH:D009584), AA (MESH:D016718), SDS (MESH:D012967), Lipid (MESH:D008055), iodoacetamide (MESH:D007460), CEs (MESH:D002788), plasmalogens (MESH:D010955), bromophenol blue (MESH:D001978), phosphatidylethanolamines (MESH:D010714), bis(monoacylglycerol)phosphates (MESH:C012786), phosphatidylinositol (MESH:D010716), agarose (MESH:D012685), MPB (MESH:C012415), DAPI (MESH:C007293), methanol (MESH:D000432), prostaglandins (MESH:D011453), FA (MESH:C030544), acrylamide (MESH:D020106), TBS (MESH:D013725), MgCl2 (MESH:D015636), ACN (MESH:C032159), sphingosine-1-phosphate (MESH:C060506), 4x (-), isopropanol (MESH:D019840), eicosapentaenoic acid (MESH:D015118), phosphatidylglycerol (MESH:D010715), lactosylceramides (MESH:D007790), sphingomyelins (MESH:D013109), -biotin (MESH:D001710), citrate (MESH:D019343), THL (MESH:D000077403), eCBs (MESH:D063388), free fatty acid (MESH:D005230), ceramides (MESH:D002518), xylene (MESH:D014992), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (MESH:C410687), EtOH (MESH:D000431), CaCl2 (MESH:D002122), DMSO (MESH:D004121), CHCl3 (MESH:D002725), docosahexaenoic acid (MESH:D004281), PFA (MESH:C003043), carbon (MESH:D002244), DAGs (MESH:D004075), Tween-20 (MESH:D011136), dichloromethane (MESH:D008752), Laemmli buffer (MESH:C088816), phosphatidylserine (MESH:D010718), phosphatidylcholine (MESH:D010713), DGLA (MESH:D015126), acetic acid (MESH:D019342), gangliosides (MESH:D005732), glycerol (MESH:D005990), monoacylglycerol (MESH:D050178), Oxylipins (MESH:D054883), Cy5 (MESH:C085321), cholesterol (MESH:D002784), Sudan Black B (MESH:C016118), hematoxylin (MESH:D006416) - **Species:** Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** 2-AG to AA, A to C - **Cell lines:** PC3 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0035) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12865325/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12865325/full.md ## References 76 references — full list in the complete paper: https://tomesphere.com/paper/PMC12865325/full.md --- Source: https://tomesphere.com/paper/PMC12865325