Research progress of plasmalogen in Alzheimer's disease

doi:10.12092/j.issn.1009-2501.2026.09.012

Abstract

Abstract:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex pathogenesis and limited current treatment options, urgently requiring new intervention targets. Plasmalogen, a naturally occurring glycerophospholipid, is widely distributed in cell membranes (such as myelin sheaths) and certain foods (such as seafood). Not only do they exhibit significant anti-inflammatory and antioxidant activities, but they have also been demonstrated to participate in memory enhancement. Growing evidence indicates that reduced plasmalogens levels are closely associated with the onset and progression of AD. Plasmalogens can target multiple key mechanisms to intervene in AD pathological processes, including clearing amyloid-β (Aβ) deposits, inhibiting apoptosis, promoting neurogenesis, and reducing excessive activation of microglia, thereby exerting neuroprotective effects. Therefore, supplementing with plasmalogens holds promise as a novel strategy for preventing and treating AD. This article aims to summarize and explore the latest research advances on plasmalogens in AD pathogenesis and therapeutic interventions, with the goal of providing new directions for further AD research and treatment.

Key words: Alzheimer's disease, microglia, plasmalogens, lipid

CLC Number:

Yinan JIN, Wenjing LI, Lihua BIAN, Jianyou GUO. Research progress of plasmalogen in Alzheimer's disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(9): 1256-1264.

Figures/Tables 2

References 68

1	Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease[J]. Lancet, 2021, 397 (10284): 1577- 1590.
2	Hetz C, Martinon F, Rodriguez D, et al. The unfolded protein response: integrating stress signals through the stress sensor IRE1α[J]. Physiol Rev, 2011, 91 (4): 1219- 1243. doi: 10.1152/physrev.00001.2011
3	Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives[J]. Biochim Biophys Acta, 2014, 1842 (8): 1219- 1231. doi: 10.1016/j.bbadis.2013.09.010
4	Hashimoto S, Saido TC. Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease[J]. Open Biol, 2018, 8 (4): 180024. doi: 10.1098/rsob.180024
5	Huang Z, Jordan JD, Zhang Q. Myelin pathology in Alzheimer's disease: potential therapeutic opportunities[J]. Aging Dis, 2024, 15 (2): 698- 713. doi: 10.14336/AD.2023.0628
6	2023 Alzheimer's disease facts and figures [J]. Alzheimers Dement, 2023, 19(4): 1598-1695.
7	Yin F. Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise[J]. FEBS J, 2023, 290 (6): 1420- 1453. doi: 10.1111/febs.16344
8	Honsho M, Yagita Y, Kinoshita N, et al. Isolation and characterization of mutant animal cell line defective in alkyl-dihydroxyacetonephosphate synthase: localization and transport of plasmalogens to post-Golgi compartments[J]. Biochim Biophys Acta, 2008, 1783 (10): 1857- 1865. doi: 10.1016/j.bbamcr.2008.05.018
9	Nagan N, Zoeller RA. Plasmalogens: biosynthesis and functions[J]. Prog Lipid Res, 2001, 40 (3): 199- 229. doi: 10.1016/S0163-7827(01)00003-0
10	Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease[J]. Biochim Biophys Acta, 2012, 1822 (9): 1442- 1452. doi: 10.1016/j.bbadis.2012.05.008
11	Rog T, Koivuniemi A. The biophysical properties of ethanolamine plasmalogens revealed by atomistic molecular dynamics simulations[J]. Biochim Biophys Acta, 2016, 1858 (1): 97- 103. doi: 10.1016/j.bbamem.2015.10.023
12	Dorninger F, König T, Scholze P, et al. Disturbed neurotransmitter homeostasis in ether lipid deficiency[J]. Hum Mol Genet, 2019, 28 (12): 2046- 2061. doi: 10.1093/hmg/ddz040
13	Leßig J, Fuchs B. Plasmalogens in biological systems: their role in oxidative processes in biological membranes, their contribution to pathological processes and aging and plasmalogen analysis[J]. Curr Med Chem, 2009, 16 (16): 2021- 2041. doi: 10.2174/092986709788682164
14	Sambra V, Echeverria F, Valenzuela A, et al. Docosahexaenoic and arachidonic acids as neuroprotective nutrients throughout the life cycle[J]. Nutrients, 2021, 13 (3): 986. doi: 10.3390/nu13030986
15	Chen C, Liao J, Xia Y, et al. Gut microbiota regulate Alzheimer's disease pathologies and cognitive disorders via PUFA-associated neuroinflammation[J]. Gut, 2022, 71 (11): 2233- 2252. doi: 10.1136/gutjnl-2021-326269
16	Liu ZG, Hualin W, Limei W, et al. Advances in research on neuron-protective role of polyunsaturated fatty acids[J]. Food Sci, 2016, 37 (7): 239.
17	Jan AT, Azam M, Rahman S, et al. Perspective insights into disease progression, diagnostics, and therapeutic approaches in Alzheimer's disease: a judicious update[J]. Front Aging Neurosci, 2017, 9, 356. doi: 10.3389/fnagi.2017.00356
18	Breijyeh Z, Karaman R. Comprehensive review on Alzheimer's disease: causes and treatment[J]. Molecules, 2020, 25 (24): 5789. doi: 10.3390/molecules25245789
19	Cras P, Kawai M, Lowery D, et al. Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein[J]. Proc Natl Acad Sci U S A, 1991, 88 (17): 7552- 7556. doi: 10.1073/pnas.88.17.7552
20	Armstrong RA. The molecular biology of senile plaques and neurofibrillary tangles in Alzheimer's disease[J]. Folia Neuropathol, 2009, 47 (4): 289- 299.
21	Chen GF, Xu TH, Yan Y, et al. Amyloid beta: structure, biology and structure-based therapeutic development[J]. Acta Pharmacol Sin, 2017, 38 (9): 1205- 1235. doi: 10.1038/aps.2017.28
22	Tabaton M, Piccini A. Role of water-soluble amyloid-beta in the pathogenesis of Alzheimer's disease[J]. Int J Exp Pathol, 2005, 86 (3): 139- 145. doi: 10.1111/j.0959-9673.2005.00428.x
23	Metaxas A, Kempf SJ. Neurofibrillary tangles in Alzheimer's disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics[J]. Neural Regen Res, 2016, 11 (10): 1579- 1581. doi: 10.4103/1673-5374.193234
24	Trejo-Lopez JA, Yachnis AT, Prokop S. Neuropathology of Alzheimer's disease[J]. Neurotherapeutics, 2022, 19 (1): 173- 185. doi: 10.1007/s13311-021-01146-y
25	Overk CR, Masliah E. Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease[J]. Biochem Pharmacol, 2014, 88 (4): 508- 516. doi: 10.1016/j.bcp.2014.01.015
26	Koch G, Spampinato D. Alzheimer disease and neuroplasticity[J]. Handb Clin Neurol, 2022, 184, 473- 479.
27	Rajendran K, Krishnan UM. Biomarkers in Alzheimer's disease[J]. Clin Chim Acta, 2024, 562, 119857. doi: 10.1016/j.cca.2024.119857
28	王刚, 齐金蕾, 刘馨雅, 等. 中国阿尔茨海默病报告2024[J]. 诊断学理论与实践, 2024, 23 (3): 219- 256.
29	Ginsberg L, Rafique S, Xuereb JH, et al. Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain[J]. Brain Res, 1995, 698 (1-2): 223- 226. doi: 10.1016/0006-8993(95)00931-F
30	Han X, Holtzman DM, McKeel DW. Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry[J]. J Neurochem, 2001, 77 (4): 1168- 1180. doi: 10.1046/j.1471-4159.2001.00332.x
31	Goodenowe DB, Cook LL, Liu J, et al. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia[J]. J Lipid Res, 2007, 48 (11): 2485- 2498. doi: 10.1194/jlr.P700023-JLR200
32	Yamashita S, Kiko T, Fujiwara H, et al. Alterations in the levels of amyloid-β, phospholipid hydroperoxide, and plasmalogen in the blood of patients with Alzheimer's disease: Possible interactions between amyloid-β and these lipids[J]. J Alzheimers Dis, 2016, 50 (2): 527- 537. doi: 10.3233/JAD-150640
33	Wood PL, Barnette BL, Kaye JA, et al. Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer's disease subjects[J]. Acta Neuropsychiatr, 2015, 27 (5): 270- 278. doi: 10.1017/neu.2015.18
34	Azad AK, Sheikh AM, Haque MA, et al. Time-dependent analysis of plasmalogens in the hippocampus of an Alzheimer's disease mouse model: a role of ethanolamine plasmalogen[J]. Brain Sci, 2021, 11 (12): 1603. doi: 10.3390/brainsci11121603
35	Dorninger F, Gundacker A, Zeitler G, et al. Ether lipid deficiency in mice produces a complex behavioral phenotype mimicking aspects of human psychiatric disorders[J]. Int J Mol Sci, 2019, 20 (16): 3929. doi: 10.3390/ijms20163929
36	Hossain MS, Mawatari S, Fujino T. Plasmalogens, the vinyl ether-linked glycerophospholipids, enhance learning and memory by regulating brain-derived neurotrophic factor[J]. Front Cell Dev Biol, 2022, 10, 828282. doi: 10.3389/fcell.2022.828282
37	Lee BY, Attwood SJ, Turnbull S, et al. Effect of varying concentrations of docosahexaenoic acid on amyloid beta (1-42) aggregation: an atomic force microscopy study[J]. Molecules, 2018, 23 (12): 3089. doi: 10.3390/molecules23123089
38	Grimm MOW, Kuchenbecker J, Rothhaar TL, et al. Plasmalogen synthesis is regulated via alkyl-dihydroxyacetonephosphate-synthase by amyloid precursor protein processing and is affected in Alzheimer's disease[J]. J Neurochem, 2011, 116 (5): 916- 925. doi: 10.1111/j.1471-4159.2010.07070.x
39	Rothhaar TL, Grösgen S, Haupenthal VJ, et al. Plasmalogens inhibit APP processing by directly affecting γ-secretase activity in Alzheimer's disease[J]. ScientificWorldJournal, 2012, 2012, 141240. doi: 10.1100/2012/141240
40	Kou J, Kovacs GG, Höftberger R, et al. Peroxisomal alterations in Alzheimer's disease[J]. Acta Neuropathol, 2011, 122 (3): 271- 283. doi: 10.1007/s00401-011-0836-9
41	Katafuchi T, Ifuku M, Mawatari S, et al. Effects of plasmalogens on systemic lipopolysaccharide-induced glial activation and β-amyloid accumulation in adult mice[J]. Ann N Y Acad Sci, 2012, 1262, 85- 92. doi: 10.1111/j.1749-6632.2012.06641.x
42	Hossain MS, Tajima A, Kotoura S, et al. Oral ingestion of plasmalogens can attenuate the LPS-induced memory loss and microglial activation[J]. Biochem Biophys Res Commun, 2018, 496 (4): 1033- 1039. doi: 10.1016/j.bbrc.2018.01.078
43	Li R, Xiong W, Li B, et al. Plasmalogen improves memory function by regulating neurogenesis in a mouse model of Alzheimer's diseases[J]. Int J Mol Sci, 2023, 24 (15): 12234. doi: 10.3390/ijms241512234
44	Hossain MS, Ifuku M, Take S, et al. Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling[J]. PLoS One, 2013, 8 (12): e83508. doi: 10.1371/journal.pone.0083508
45	Che H, Li Q, Zhang T, et al. A comparative study of EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine on Aβ42 induced cognitive deficiency in a rat model of Alzheimer's disease[J]. Food Funct, 2018, 9 (5): 3008- 3017. doi: 10.1039/C8FO00643A
46	Abdou HM, Hamaad FA, Elmageed GMA, et al. Efficacy of plasmalogens on monosodium glutamate-induced neurotoxicity in male rats through NF-κB and p38 MAPK signaling pathways[J]. Oxid Med Cell Longev, 2025, 2025, 3673280. doi: 10.1155/omcl/3673280
47	Liu Y, Cong P, Zhang T, et al. Plasmalogen attenuates the development of hepatic steatosis and cognitive deficit through mechanism involving p75NTR inhibition[J]. Redox Biol, 2021, 43, 102002. doi: 10.1016/j.redox.2021.102002
48	Yu J, Su J, Zhang Y, et al. Mitigating effects of plasmalogens on age-related cognitive impairment[J]. J Funct Foods, 2025, 128, 106790. doi: 10.1016/j.jff.2025.106790
49	Bestard Escalas J. Role of membrane lipids in colon differentiation unravelled by mass spectrometry imaging: Arachidonic acid beyond inflammation [D]. Palma: Universitat de les Illes Balears, 2019.
50	Amemori T, Jendelova P, Ruzicka J, et al. Alzheimer's disease: mechanism and approach to cell therapy[J]. Int J Mol Sci, 2015, 16 (11): 26417- 26451. doi: 10.3390/ijms161125961
51	Shirokov A, Zlatogosrkaya D, Adushkina V, et al. Plasmalogens improve lymphatic clearance of amyloid beta from mouse brain and cognitive functions[J]. Int J Mol Sci, 2024, 25 (23): 12552. doi: 10.3390/ijms252312552
52	Takekoshi H, Fujishima M, Miyazawa T, et al. Simultaneous intake of chlorella and ascidian ethanolamine plasmalogen accelerates activation of BDNF-TrkB-CREB signaling in rats[J]. Molecules, 2024, 29 (2): 357. doi: 10.3390/molecules29020357
53	Ifuku M, Katafuchi T, Mawatari S, et al. Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice[J]. J Neuroinflammation, 2012, 9, 197. doi: 10.1186/1742-2094-9-197
54	Hossain MS, Abe Y, Ali F, et al. Reduction of ether-type glycerophospholipids, plasmalogens, by NF-κB signal leading to microglial activation[J]. J Neurosci, 2017, 37 (15): 4074- 4092. doi: 10.1523/JNEUROSCI.3941-15.2017
55	Tremblay MÈ, Almsherqi ZA, Deng Y. Plasmalogens and platelet-activating factor roles in chronic inflammatory diseases[J]. Biofactors, 2022, 48 (6): 1203- 1216. doi: 10.1002/biof.1916
56	Yamagiwa N, Kobayashi H, Okabayashi H, et al. Phosphatidylcholine-plasmalogen-oleic acid has protective effects against arachidonic acid-induced cytotoxicity[J]. Biol Pharm Bull, 2022, 45 (5): 643- 648. doi: 10.1248/bpb.b22-00035
57	Gu J, Chen L, Sun R, et al. Plasmalogens eliminate aging-associated synaptic defects and microglia-mediated neuroinflammation in mice[J]. Front Mol Biosci, 2022, 9, 815320. doi: 10.3389/fmolb.2022.815320
58	Fujino T, Hossain MS, Mawatari S. Therapeutic efficacy of plasmalogens for Alzheimer's disease, mild cognitive impairment, and Parkinson’s disease in conjunction with a new hypothesis for the etiology of Alzheimer's disease[J]. Adv Exp Med Biol, 2020, 1299, 195- 212. doi: 10.1007/978-3-030-60204-8_14
59	Hossain MS, Mineno K, Katafuchi T. Neuronal orphan G-protein coupled receptor proteins mediate plasmalogens-induced activation of ERK and Akt signaling[J]. PLoS One, 2016, 11 (3): e0150846. doi: 10.1371/journal.pone.0150846
60	Fujino M, Fukuda J, Isogai H, et al. Orally administered plasmalogens alleviate negative mood states and enhance mental concentration: a randomized, double-blind, placebo-controlled trial[J]. Front Cell Dev Biol, 2022, 10, 894734. doi: 10.3389/fcell.2022.894734
61	Smith T, Knudsen KJ, Ritchie SA. A novel inducible animal model for studying chronic plasmalogen deficiency associated with Alzheimer's disease[J]. Brain Res, 2024, 1843, 149132. doi: 10.1016/j.brainres.2024.149132
62	Hossain MS, Mawatari S, Honsho M, et al. KIT-13, a novel plasmalogen derivative, attenuates neuroinflammation and amplifies cognition[J]. Front Cell Dev Biol, 2024, 12, 1443536. doi: 10.3389/fcell.2024.1443536
63	Fujino T, Yamada T, Asada T, et al. Efficacy and blood plasmalogen changes by oral administration of plasmalogen in patients with mild Alzheimer's disease and mild cognitive impairment: a multicenter, randomized, double-blind, placebo-controlled trial[J]. EBioMedicine, 2017, 17, 199- 205. doi: 10.1016/j.ebiom.2017.02.012
64	Meletis CD. Alkyl-acylglycerols and the important clinical ramifications of raising plasmalogens in dementia and Alzheimer's disease[J]. Integr Med (Encinitas), 2020, 19 (3): 12- 16.
65	Ouma S, Tsuboi Y, Mawatari S, et al. Effectiveness of blood plasmalogen in differentiation among mild cognitive impairment, mild Alzheimer's disease and normal elderly[J]. J Neurol Sci, 2017, 381, 770.
66	Bergstrom S, Blomstrand R. The intestinal absorption and metabolism of chimyl alcohol in the rat[J]. Acta Physiol Scand, 1956, 38 (2): 166- 172. doi: 10.1111/j.1748-1716.1957.tb01380.x
67	Brites P, Ferreira AS, da Silva TF, et al. Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice[J]. PLoS One, 2011, 6 (12): e28539. doi: 10.1371/journal.pone.0028539
68	Hoffman-Kuczynski B, Reo NV. Administration of myo-inositol plus ethanolamine elevates phosphatidylethanolamine plasmalogen in the rat cerebellum[J]. Neurochem Res, 2005, 30 (1): 47- 60. doi: 10.1007/s11064-004-9685-4

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